Tetrahydronaphthalene estrogen receptor modulators and uses thereof

ABSTRACT

Described herein are tetrahydronaphthalene compounds with estrogen receptor modulation activity or function having the Formula I structure: 
     
       
         
         
             
             
         
       
         
         
           
             and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such estrogen receptor modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

CROSS REFERENCE TO RELATED APPLICATIONS

This non-provisional application filed under 37 CFR § 1.53(b), claimsthe benefit under 35 U.S.C. § 119(e) of U.S. Provisional ApplicationSer. No. 62/252,707 filed on 9 Nov. 2015, which is incorporated byreference in entirety.

FIELD OF THE INVENTION

Described herein are compounds, including pharmaceutically acceptablesalts, solvates, metabolites, prodrugs thereof, pharmaceuticalcompositions comprising such compounds, and methods of using suchcompounds to treat, prevent or diagnose diseases or conditions that areestrogen sensitive, estrogen receptor dependent or estrogen receptormediated in combination with other therapeutic agents.

BACKGROUND OF THE INVENTION

The estrogen receptor (“ER”) is a ligand-activated transcriptionalregulatory protein that mediates induction of a variety of biologicaleffects through its interaction with endogenous estrogens. Endogenousestrogens include 1713 (beta)-estradiol and estrones. ER has been foundto have two isoforms, ER-α (alpha) and ER-β (beta). Estrogens andestrogen receptors are implicated in a number of diseases or conditions,such as breast cancer, lung cancer, ovarian cancer, colon cancer,prostate cancer, endometrial cancer, uterine cancer, as well as othersdiseases or conditions. There is a need for new ER-α targeting agentsthat have activity in the setting of metastatic disease and acquiredresistance.

SUMMARY OF THE INVENTION

The invention relates generally to tetrahydronaphthalene compounds withestrogen receptor modulation activity or function and having the FormulaI structure:

and stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, with the substituents and structural features described herein.

An aspect of the invention is a pharmaceutical composition of a FormulaI compound and a pharmaceutically acceptable carrier, glidant, diluent,or excipient.

An aspect of the invention is a process for making a Formula I compoundor a pharmaceutical composition comprising a Formula I compound.

An aspect of the invention is a method of treating an ER-related diseaseor disorder in a patient comprising administering a therapeuticallyeffective amount of the pharmaceutical composition to a patient with anER-related disease or disorder.

An aspect of the invention is a kit for treating a condition mediated byan estrogen receptor, comprising:

a) a pharmaceutical composition comprising a Formula I compound; and

b) instructions for use.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature, patents, and similar materials differs from or contradictsthis application, including but not limited to defined terms, termusage, described techniques, or the like, this application controls.Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the invention, suitable methods and materials aredescribed below. All publications, patent applications, patents, andother references mentioned herein are incorporated by reference in theirentirety. The nomenclature used in this Application is based on IUPACsystematic nomenclature, unless indicated otherwise.

Definitions

When indicating the number of substituents, the term “one or more”refers to the range from one substituent to the highest possible numberof substitution, i.e. replacement of one hydrogen up to replacement ofall hydrogens by substituents. The term “substituent” denotes an atom ora group of atoms replacing a hydrogen atom on the parent molecule. Theterm “substituted” denotes that a specified group bears one or moresubstituents. Where any group may carry multiple substituents and avariety of possible substituents is provided, the substituents areindependently selected and need not to be the same. The term“unsubstituted” means that the specified group bears no substituents.The term “optionally substituted” means that the specified group isunsubstituted or substituted by one or more substituents, independentlychosen from the group of possible substituents. When indicating thenumber of substituents, the term “one or more” means from onesubstituent to the highest possible number of substitution, i.e.replacement of one hydrogen up to replacement of all hydrogens bysubstituents.

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms (C₁-C₁₂), wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below. In anotherembodiment, an alkyl radical is one to eight carbon atoms (C₁-C₈), orone to six carbon atoms (C₁-C₆). Examples of alkyl groups include, butare not limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl(n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂),1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu,i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

The term “alkyldiyl” as used herein refers to a saturated linear orbranched-chain divalent hydrocarbon radical of about one to twelvecarbon atoms (C₁-C₁₂), wherein the alkyldiyl radical may be optionallysubstituted independently with one or more substituents described below.In another embodiment, an alkyldiyl radical is one to eight carbon atoms(C₁-C₈), or one to six carbon atoms (C₁-C₆). Examples of alkyldiylgroups include, but are not limited to, methylene (—CH₂—), ethylene(—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), and the like. An alkyldiyl groupmay also be referred to as an “alkylene” group. The term“fluoroalkyldiyl” as used herein refers to an alkyldiyl radicalsubstituted with one or more fluorine atoms.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to eight carbon atoms (C₂-C₈) with at leastone site of unsaturation, i.e., a carbon-carbon, sp² double bond,wherein the alkenyl radical may be optionally substituted independentlywith one or more substituents described herein, and includes radicalshaving “cis” and “trans” orientations, or alternatively, “E” and “Z”orientations. Examples include, but are not limited to, ethylenyl orvinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), and the like.

The terms “alkenylene” or “alkenyldiyl” refer to a linear orbranched-chain divalent hydrocarbon radical of two to eight carbon atoms(C₂-C₈) with at least one site of unsaturation, i.e., a carbon-carbon,sp² double bond, wherein the alkenylene radical may be optionallysubstituted independently with one or more substituents describedherein, and includes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations. Examples include, but are notlimited to, ethylenylene or vinylene (—CH═CH—), allyl (—CH₂CH═CH—), andthe like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to eight carbon atoms (C₂-C₈) with at least one site ofunsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynylradical may be optionally substituted independently with one or moresubstituents described herein. Examples include, but are not limited to,ethynyl (—C≡CH), propynyl (propargyl, —CH₂C≡CH), and the like.

The term “alkynylene” or “alkynyldiyl” refer to a linear or brancheddivalent hydrocarbon radical of two to eight carbon atoms (C₂-C₈) withat least one site of unsaturation, i.e., a carbon-carbon, sp triplebond, wherein the alkynylene radical may be optionally substitutedindependently with one or more substituents described herein. Examplesinclude, but are not limited to, ethynylene (—C≡C—), propynylene(propargylene, —CH₂C≡C—), and the like.

The terms “carbocycle”, “carbocyclyl”, “carbocyclic ring” and“cycloalkyl” refer to a monovalent non-aromatic, saturated or partiallyunsaturated ring having 3 to 12 carbon atoms (C₃-C₁₂) as a monocyclicring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycleshaving 7 to 12 atoms can be arranged, for example, as a bicyclo [4,5],[5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10ring atoms can be arranged as a bicyclo [5,6] or [6,6] system, or asbridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane andbicyclo[3.2.2]nonane. Spiro carbocyclyl moieties are also includedwithin the scope of this definition. Examples of spiro carbocyclylmoieties include [2.2]pentanyl, [2.3]hexanyl, and [2.4]heptanyl.Examples of monocyclic carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and thelike. Carbocyclyl groups are optionally substituted independently withone or more substituents described herein.

The term “carbocyclyldiyl” refers to a divalent non-aromatic, saturatedor partially unsaturated ring having 3 to 12 carbon atoms (C₃-C₁₂) as amonocyclic ring or 7 to 12 carbon atoms as a bicyclic ring.

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms (C₆-C₂₀) derived by the removal of one hydrogen atom from a singlecarbon atom of a parent aromatic ring system. Some aryl groups arerepresented in the exemplary structures as “Ar”. Aryl includes bicyclicradicals comprising an aromatic ring fused to a saturated, partiallyunsaturated ring, or aromatic carbocyclic ring. Typical aryl groupsinclude, but are not limited to, radicals derived from benzene (phenyl),substituted benzenes, naphthalene, anthracene, biphenyl, indenyl,indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and thelike. Aryl groups are optionally substituted independently with one ormore substituents described herein.

The terms “arylene” or “aryldiyl” mean a divalent aromatic hydrocarbonradical of 6-20 carbon atoms (C₆-C₂₀) derived by the removal of twohydrogen atom from a two carbon atoms of a parent aromatic ring system.Some aryldiyl groups are represented in the exemplary structures as“Ar”. Aryldiyl includes bicyclic radicals comprising an aromatic ringfused to a saturated, partially unsaturated ring, or aromaticcarbocyclic ring. Typical aryldiyl groups include, but are not limitedto, radicals derived from benzene (phenyldiyl), substituted benzenes,naphthalene, anthracene, biphenylene, indenylene, indanylene,1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like.Aryldiyl groups are also referred to as “arylene”, and are optionallysubstituted with one or more substituents described herein.

The terms “heterocycle,” “heterocyclyl” and “heterocyclic ring” are usedinterchangeably herein and refer to a saturated or a partiallyunsaturated (i.e., having one or more double and/or triple bonds withinthe ring) carbocyclic radical of 3 to about 20 ring atoms in which atleast one ring atom is a heteroatom selected from nitrogen, oxygen,phosphorus and sulfur, the remaining ring atoms being C, where one ormore ring atoms is optionally substituted independently with one or moresubstituents described below. A heterocycle may be a monocycle having 3to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selectedfrom N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), forexample: a bicyclo [4,5], [5,5], [5,6], or [6,6] system. Heterocyclesare described in Paquette, Leo A.; “Principles of Modern HeterocyclicChemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3,4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series ofMonographs” (John Wiley & Sons, New York, 1950 to present), inparticular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960)82:5566. “Heterocyclyl” also includes radicals where heterocycleradicals are fused with a saturated, partially unsaturated ring, oraromatic carbocyclic or heterocyclic ring. Examples of heterocyclicrings include, but are not limited to, morpholin-4-yl, piperidin-1-yl,piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one,pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl,azocan-1-yl, azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl,[1,4]diazepan-1-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl,thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl,dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolylquinolizinyl and N-pyridyl ureas. Spiro heterocyclyl moieties are alsoincluded within the scope of this definition. Examples of spiroheterocyclyl moieties include azaspiro[2.5]octanyl andazaspiro[2.4]heptanyl. Examples of a heterocyclic group wherein 2 ringatoms are substituted with oxo (═O) moieties are pyrimidinonyl and1,1-dioxo-thiomorpholinyl. The heterocycle groups herein are optionallysubstituted independently with one or more substituents describedherein.

The term “heterocyclyldiyl” refers to a divalent, saturated or apartially unsaturated (i.e., having one or more double and/or triplebonds within the ring) carbocyclic radical of 3 to about 20 ring atomsin which at least one ring atom is a heteroatom selected from nitrogen,oxygen, phosphorus and sulfur, the remaining ring atoms being C, whereone or more ring atoms is optionally substituted independently with oneor more substituents as described.

The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-,or 7-membered rings, and includes fused ring systems (at least one ofwhich is aromatic) of 5-20 atoms, containing one or more heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Examples ofheteroaryl groups are pyridinyl (including, for example,2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl(including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl,triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups areoptionally substituted independently with one or more substituentsdescribed herein.

The term “heteroaryldiyl” refers to a divalent aromatic radical of 5-,6-, or 7-membered rings, and includes fused ring systems (at least oneof which is aromatic) of 5-20 atoms, containing one or more heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

The heterocycle or heteroaryl groups may be carbon (carbon-linked), ornitrogen (nitrogen-linked) bonded where such is possible. By way ofexample and not limitation, carbon bonded heterocycles or heteroarylsare bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5,or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline.

By way of example and not limitation, nitrogen bonded heterocycles orheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or 3-carboline.

The terms “treat” and “treatment” refer to therapeutic treatment,wherein the object is to slow down (lessen) an undesired physiologicalchange or disorder, such as the development or spread of arthritis orcancer. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, delay or slowing of disease progression, ameliorationor palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment. Those in need of treatment include those with the conditionor disorder.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats the particulardisease, condition, or disorder, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease, condition, ordisorder, or (iii) prevents or delays the onset of one or more symptomsof the particular disease, condition, or disorder described herein. Inthe case of cancer, the therapeutically effective amount of the drug mayreduce the number of cancer cells; reduce the tumor size; inhibit (i.e.,slow to some extent and preferably stop) cancer cell infiltration intoperipheral organs; inhibit (i.e., slow to some extent and preferablystop) tumor metastasis; inhibit, to some extent, tumor growth; and/orrelieve to some extent one or more of the symptoms associated with thecancer. To the extent the drug may prevent growth and/or kill existingcancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy,efficacy can be measured, for example, by assessing the time to diseaseprogression (TTP) and/or determining the response rate (RR).

The terms “cancer” refers to or describe the physiological condition inmammals that is typically characterized by unregulated cell growth. A“tumor” comprises one or more cancerous cells. Examples of cancerinclude, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma,and leukemia or lymphoid malignancies. More particular examples of suchcancers include squamous cell cancer (e.g., epithelial squamous cellcancer), lung cancer including small-cell lung cancer, non-small celllung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinomaof the lung, cancer of the peritoneum, hepatocellular cancer, gastric orstomach cancer including gastrointestinal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladdercancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectalcancer, endometrial or uterine carcinoma, salivary gland carcinoma,kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer,hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head andneck cancer.

“Hematological malignancies” (British spelling “Haematological”malignancies) are the types of cancer that affect blood, bone marrow,and lymph nodes. As the three are intimately connected through theimmune system, a disease affecting one of the three will often affectthe others as well: although lymphoma is a disease of the lymph nodes,it often spreads to the bone marrow, affecting the blood. Hematologicalmalignancies are malignant neoplasms (“cancer”), and they are generallytreated by specialists in hematology and/or oncology. In some centers“Hematology/oncology” is a single subspecialty of internal medicinewhile in others they are considered separate divisions (there are alsosurgical and radiation oncologists). Not all hematological disorders aremalignant (“cancerous”); these other blood conditions may also bemanaged by a hematologist. Hematological malignancies may derive fromeither of the two major blood cell lineages: myeloid and lymphoid celllines. The myeloid cell line normally produces granulocytes,erythrocytes, thrombocytes, macrophages and mast cells; the lymphoidcell line produces B, T, NK and plasma cells. Lymphomas, lymphocyticleukemias, and myeloma are from the lymphoid line, while acute andchronic myelogenous leukemia, myelodysplastic syndromes andmyeloproliferative diseases are myeloid in origin. Leukemias includeAcute lymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML),Chronic lymphocytic leukemia (CLL), Chronic myelogenous leukemia (CML),Acute monocytic leukemia (AMOL) and small lymphocytic lymphoma (SLL).Lymphomas include Hodgkin's lymphomas (all four subtypes) andNon-Hodgkin's lymphomas (NHL, all subtypes).

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer, regardless of mechanism of action. Classes ofchemotherapeutic agents include, but are not limited to: alkylatingagents, antimetabolites, spindle poison plant alkaloids,cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies,photosensitizers, and kinase inhibitors. Chemotherapeutic agents includecompounds used in “targeted therapy” and conventional chemotherapy.Examples of chemotherapeutic agents include: ibrutinib (IMBRUVICA™,APCI-32765, Pharmacyclics Inc./Janssen Biotech Inc.; CAS Reg. No.936563-96-1, U.S. Pat. No. 7,514,444), idelalisib (ZYDELIG®, CAL-101, GS1101, GS-1101, Gilead Sciences Inc.; CAS Reg. No. 1146702-54-6),erlotinib (TARCEVA®, Genentech/OSI Pharm.), docetaxel (TAXOTERE®,Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS Reg. No.51-21-8), gemcitabine (GEMZAR®, Lilly), PD-0325901 (CAS No. 391210-10-9,Pfizer), cisplatin (Platinol®, (SP-4-2)-diamminedichloroplatinum(II),cis-diamine, dichloroplatinum(II), CAS No. 15663-27-1), carboplatin (CASNo. 41575-94-4), paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology,Princeton, N.J.), trastuzumab (HERCEPTIN®, Genentech), temozolomide(4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide, CAS No. 85622-93-1, TEMODAR®,TEMODAL®, Schering Plough), tamoxifen((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine,NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCIN®, CAS No.23214-92-8), Akti-1/2, HPPD, and rapamycin.

Chemotherapeutic agents include inhibitors of B-cell receptor targetssuch as BTK, Bcl-2 and JAK inhibitors.

More examples of chemotherapeutic agents include: oxaliplatin(ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent(SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinibmesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, AstraZeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235(PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin(folinic acid), rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib(TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR™, SCH66336, Schering Plough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs),gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11,Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANE™(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.),vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chlorambucil, AG1478,AG1571 (SU 5271; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib(GlaxoSmithKline), canfosfamide (TELCYTA®, Telik), thiotepa andcyclosphosphamide (CYTOXAN®, NEOSAR®); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethi ophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analog topotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogs, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlornaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, calicheamicin gammall, calicheamicin omegall (Angew Chem.Intl. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A;bisphosphonates, such as clodronate; an esperamicin; as well asneocarzinostatin chromophore and related chromoprotein enediyneantibiotic chromophores), aclacinomysins, actinomycin, authramycin,azaserine, bleomycins, cactinomycin, carabicin, carminomycin,carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin,marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofiran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone;vincristine; vinorelbine (NAVELBINE®); novantrone; teniposide;edatrexate; daunomycin; aminopterin; capecitabine (XELODA®, Roche);ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO); retinoids such as retinoic acid; andpharmaceutically acceptable salts, acids and derivatives of any of theabove.

Also included in the definition of“chemotherapeutic agent” are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including NOLVADEX®;tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifinecitrate) and selective estrogen receptor modulators (SERDs) such asfulvestrant (FASLODEX®, Astra Zeneca); (ii) aromatase inhibitors thatinhibit the enzyme aromatase, which regulates estrogen production in theadrenal glands, such as, for example, 4(5)-imidazoles,aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane;Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA®(letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii)anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide,and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleosidecytosine analog); (iv) protein kinase inhibitors such as MEK inhibitors,such as cobimetinib (WO 2007/044515); (v) lipid kinase inhibitors, suchas taselisib (GDC-0032, Genentech Inc.); (vi) antisenseoligonucleotides, particularly those which inhibit expression of genesin signaling pathways implicated in aberrant cell proliferation, forexample, PKC-alpha, Raf and H-Ras, such as oblimersen (GENASENSE®, GentaInc.); (vii) ribozymes such as VEGF expression inhibitors (e.g.,ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as genetherapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®;PROLEUKIN® rIL-2; topoisomerase 1 inhibitors such as LURTOTECAN®;ABARELIX® rmRH; (ix) anti-angiogenic agents such as bevacizumab(AVASTIN®, Genentech); and pharmaceutically acceptable salts, acids andderivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” aretherapeutic antibodies such as alemtuzumab (Campath), bevacizumab(AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab(VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec),pertuzumab (PERJETA™, 2C4, Genentech), trastuzumab (HERCEPTIN®,Genentech), trastuzumab emtansine (KADCYLA®, Genentech Inc.), andtositumomab (BEXXAR, Corixia).

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. Metabolites of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result for example from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered compound.Accordingly, the invention includes metabolites of compounds of theinvention, including compounds produced by a process comprisingcontacting a Formula I compound of this invention with a mammal for aperiod of time sufficient to yield a metabolic product thereof.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand 1 or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity. Enantiomers may be separated from a racemic mixture bya chiral separation method, such as supercritical fluid chromatography(SFC). Assignment of configuration at chiral centers in separatedenantiomers may be tentative as depicted in Table 1 structures forillustrative purposes, while stereochemistry is definitivelyestablished, such as from x-ray crystallographic data.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

The term “pharmaceutically acceptable salts” denotes salts which are notbiologically or otherwise undesirable. Pharmaceutically acceptable saltsinclude both acid and base addition salts. The phrase “pharmaceuticallyacceptable” indicates that the substance or composition must becompatible chemically and/or toxicologically, with the other ingredientscomprising a formulation, and/or the mammal being treated therewith.

The term “pharmaceutically acceptable acid addition salt” denotes thosepharmaceutically acceptable salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid, and organic acids selected fromaliphatic, cycloaliphatic, aromatic, aryl-aliphatic, heterocyclic,carboxylic, and sulfonic classes of organic acids such as formic acid,acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid,pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid,ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamicacid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonicacid “mesylate”, ethanesulfonic acid, p-toluenesulfonic acid, andsalicyclic acid.

The term “pharmaceutically acceptable base addition salt” denotes thosepharmaceutically acceptable salts formed with an organic or inorganicbase. Examples of acceptable inorganic bases include sodium, potassium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, andaluminum salts. Salts derived from pharmaceutically acceptable organicnontoxic bases includes salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, and polyamine resins

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethylacetate (EtOAc), acetic acid (AcOH), andethanolamine.

The term “EC₅₀” is the half maximal effective concentration” and denotesthe plasma concentration of a particular compound required for obtaining50% of the maximum of a particular effect in vivo.

The term “Ki” is the inhibition constant and denotes the absolutebinding affinity of a particular inhibitor to a receptor. It is measuredusing competition binding assays and is equal to the concentration wherethe particular inhibitor would occupy 50% of the receptors if nocompeting ligand (e.g. a radioligand) was present. Ki values can beconverted logarithmically to pKi values (−log Ki), in which highervalues indicate exponentially greater potency.

The term “IC₅₀” is the half maximal inhibitory concentration and denotesthe concentration of a particular compound required for obtaining 50%inhibition of a biological process in vitro. IC₅₀ values can beconverted logarithmically to pIC₅₀ values (−log IC₅₀), in which highervalues indicate exponentially greater potency. The IC₅₀ value is not anabsolute value but depends on experimental conditions e.g.concentrations employed, and can be converted to an absolute inhibitionconstant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol.(1973) 22:3099). Other percent inhibition parameters, such as IC₇₀,IC₉₀, etc., may be calculated.

The terms “compound of this invention,” and “compounds of the presentinvention” and “compounds of Formula I” include compounds of Formulas Iand stereoisomers, geometric isomers, tautomers, solvates, metabolites,and pharmaceutically acceptable salts and prodrugs thereof.

Any formula or structure given herein, including Formula I compounds, isalso intended to represent hydrates, solvates, and polymorphs of suchcompounds, and mixtures thereof.

Any formula or structure given herein, including Formula I compounds, isalso intended to represent unlabeled forms as well as isotopicallylabeled forms of the compounds. Isotopically labeled compounds havestructures depicted by the formulas given herein except that one or moreatoms are replaced by an atom having a selected atomic mass or massnumber. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as, but not limited to 2H(deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S,36Cl, and 125I. Various isotopically labeled compounds of the presentinvention, for example those into which radioactive isotopes such as 3H,13C, and 14C are incorporated. Such isotopically labeled compounds maybe useful in metabolic studies, reaction kinetic studies, detection orimaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. Deuterium labeled or substituted therapeutic compounds of theinvention may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism, and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements. An18F labeled compound may be useful for PET or SPECT studies.Isotopically labeled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. Further, substitution with heavierisotopes, particularly deuterium (i.e., 2H or D) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements or animprovement in therapeutic index. It is understood that deuterium inthis context is regarded as a substituent in the compound of the formula(I). The concentration of such a heavier isotope, specificallydeuterium, may be defined by an isotopic enrichment factor. In thecompounds of this invention any atom not specifically designated as aparticular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Accordingly, inthe compounds of this invention any atom specifically designated as adeuterium (D) is meant to represent deuterium.

Estrogen Receptor

Estrogen receptor alpha (ER-α; NR3A1) and estrogen receptor beta (ER-β;NR3A2) are steroid hormone receptors, which are members of the largenuclear receptor superfamily. Nuclear receptors share a common modularstructure, which minimally includes a DNA binding domain (DBD) and aligand binding domain (LBD). Steroid hormone receptors are soluble,intracellular proteins that act as ligand-regulated transcriptionfactors. Vertebrates contain five closely related steroid hormonereceptors (estrogen receptor, androgen receptor, progesterone receptor,glucocorticoid receptor, mineralcorticoid receptor), which regulate awide spectrum of reproductive, metabolic and developmental activities.The activities of ER are controlled by the binding of endogenousestrogens, including 17 β-estradiol and estrones. The ER-α (alpha) geneis located on 6q25.1 and encodes a 595 AA protein. The ER-β gene resideson chromosome 14q23.3 and produces a 530 AA protein. However, due toalternative splicing and translation start sites, each of these genescan give rise to multiple isoforms. In addition to the DNA bindingdomain (called C domain) and ligand binding domain (E domain) thesereceptors contain an N-terminal (A/B) domain, a hinge (D) domain thatlinks the C and E domains, and a C-terminal extension (F domain)(Gronemeyer and Laudet; Protein Profile 2: 1173-1308, 1995). While the Cand E domains of ER-α and ER-β are quite conserved (95% and 55% aminoacid identity, respectively), conservation of the A/B, D and F domainsis poor (below 30% amino acid identity). Both receptors are involved inthe regulation and development of the female reproductive tract but alsoplay various roles in the central nervous system, cardiovascular systemsand bone metabolism.

The ligand binding pocket of steroid hormone receptors is deeply buriedwithin the ligand binding domain. Upon binding, the ligand becomes partof the hydrophobic core of this domain. Consequently most steroidhormone receptors are instable in the absence of hormone and requireassistance from chaperones, such as Hsp90, in order to maintainhormone-binding competency. The interaction with Hsp90 also controlsnuclear translocation of these receptors. Ligand-binding stabilizes thereceptor and initiates sequential conformational changes that releasethe chaperones, alter the interactions between the various receptordomains and remodel protein interaction surfaces that allow thesereceptors to translocate into the nucleus, bind DNA and engage ininteractions with chromatin remodeling complexes and the transcriptionalmachinery. Although ER can interact with Hsp90, this interaction is notrequired for hormone binding and, dependent on the cellular context,apo-ER can be both cytoplasmic and nuclear. Biophysical studiesindicated that DNA binding rather than ligand binding contributes to thestability of the receptor (Greenfield et al., 2001) (Biochemistry 40:6646-6652).

ER can interact with DNA either directly by binding to a specific DNAsequence motif called estrogen response element (ERE) (classicalpathway), or indirectly via protein-protein interactions (nonclassicalpathway) (Welboren et al., Endocrine-Related Cancer 16: 1073-1089,2009). In the nonclassical pathway, ER has been shown to tether to othertranscription factors including SP-1, AP-1 and NF-κB. These interactionsappear to play critical roles in the ability of ER to regulate cellproliferation and differentiation.

Both types of ER DNA interactions can result in gene activation orrepression dependent on the transcriptional coregulators that arerecruited by the respective ER-ERE complex (Klinge, Steroid 65: 227-251,2000). The recruitment of coregulators is primarily mediated by twoprotein interaction surfaces, the AF2 and AF1. AF2 is located in the ERE-domain and its conformation is directly regulated by the ligand(Brzozowski et al., (1997) Nature 389: 753-758,). Full agonists appearto promote the recruitment of co-activators, whereas weak agonists andantagonists facilitate the binding of co-repressors. The regulation ofprotein with the AF1 is less well understood but can be controlled byserine phosphorylation (Ward and Weigel, (2009) Biofactors 35: 528-536).One of the involved phosphorylation sites (S118) appears to control thetranscriptional activity of ER in the presence of antagonists such astamoxifen, which plays an important role in the treatment of breastcancer. While full agonists appear to arrest ER in certain conformation,weak agonists tend to maintain ER in equilibrium between differentconformations, allowing cell-dependent differences in co-regulatorrepertoires to modulate the activity of ER in a cell-dependent manner(Tamrazi et al., Mol. Endocrinol. 17: 2593-2602, 2003). Interactions ofER with DNA are dynamic and include, but are not limited to, thedegradation of ER by the proteasome (Reid et al., Mol Cell 11: 695-707,2003). The degradation of ER with ligands provides an attractivetreatment strategy for diseases or conditions that areestrogen-sensitive and/or resistant to available anti-hormonaltreatments. ER signaling is crucial for the development and maintenanceof female reproductive organs including breasts, ovulation andthickening of the endometrium. ER signaling also has a role in bonemass, lipid metabolism, cancers, etc. About 70% of breast cancersexpress ER-α (alpha) (ER-α positive) and are dependent on estrogens forgrowth and survival. Other cancers also are thought to be dependent onER-α signaling for growth and survival, such as for example ovarian andendometrial cancers. The ER-α antagonist tamoxifen has been used totreat early and advanced ER-α positive breast cancer in both pre- andpost-menopausal women. Fulvestrant (FASLODEX®, AstraZeneca) asteroid-based ER antagonist is used to treat breast cancer in womenwhich have progressed despite therapy with tamoxifen (Howell A. (2006)Endocr Relat Cancer; 13:689-706; U.S. Pat. Nos. 6,774,122; 7,456,160;8,329,680; 8,466,139). Steroidal and non-steroidal aromatase inhibitorsare also used to treat cancers in humans. In some embodiments, thesteroidal and non-steroidal aromatase inhibitors block the production ofestrogen from androstenedione and testosterone in post-menopausal women,thereby blocking ER dependent growth in the cancers. In addition tothese anti-hormonal agents, progressive ER positive breast cancer istreated in some cases with a variety of other chemotherapeutics, such asfor example, the anthracylines, platins, taxanes. In some cases, ERpositive breast cancers that harbor genetic amplification of theERB-B/HER2 tyrosine kinase receptor are treated with the monoclonalantibody trastuzumab (Herceptin®, Genentech Inc.) or the small moleculepan-ERB-B inhibitor lapatinib (TYKERB®, GlaxoSmith Kline Corp.). Despitethis battery of anti-hormonal, chemotherapeutic and small-molecule andantibody-based targeted therapies, many women with ER-α positive breastdevelop progressive metastatic disease and are in need of new therapies.Importantly, the majority of ER positive tumors that progress onexisting anti-hormonal, as well as and other therapies, are thought toremain dependent on ER-α for growth and survival. Thus, there is a needfor new ER-α targeting agents that have activity in the setting ofmetastatic disease and acquired resistance. In one aspect, describedherein are compounds that are selective estrogen receptor modulators(SERMs). In specific embodiments, the SERMs described herein areselective estrogen receptor degraders (SERDs). In some embodiments, incell-based assays the compounds described herein result in a reductionin steady state ER-α levels (i.e. ER degradation) and are useful in thetreatment of estrogen sensitive diseases or conditions and/or diseasesor conditions that have developed resistant to anti-hormonal therapies.

Most breast cancer patients are treated with agents that either blockestrogen synthesis (e.g., aromatase inhibitors; AIs) or antagonize theeffects of estradiol via competitive ER binding (e.g., tamoxifen)(Puhalla S, et al Mol Oncol 2012; 6(2):222-236). Despite the welldocumented therapeutic utility of these agents in various stages ofdisease, many ER+ breast cancers recur and patients eventually succumb.Recently, next generation whole genome and targeted sequencing hasidentified ESR1 (estrogen receptor alpha gene) mutations in up to 20% oftumors from patients with advanced breast cancer who have progressed onendocrine therapies, largely aromatase inhibitors (Li S, et al. Cell Rep(2013); 4(6): 1116-1130; Merenbakh-Lamin K, et al. Cancer Res (2013);73(23): 6856-6864; Robinson D R, et al. Nat Genet (2013); 45(12):1446-1451; Toy W, et al. Nat Genet (2013); 45(12): 1439-1445; JeselsohnR, et al. Clin Cancer Res (2014); 20: 1757-1767). These ligand-bindingdomain (LBD) mutations confer high basal activity of the apo-receptorrendering them ligand-independent and thus active in the setting of lowestradiol. There is a need for therapies that target ER signaling withrobust activity in the setting of progressive disease post AI ortamoxifen treatment including the subset of patients harboring ESR1mutant tumors.

In some embodiments, Formula I compounds disclosed herein are used inmethods for treating a hormone resistant-estrogen receptor (ER) positivebreast cancer in a patient characterized as having a mutation in theESR1 gene, comprising administering a therapeutically-effective amountof a Formula I compound. In some embodiments, the mutation in the ESR1gene results in an ER polypeptide having an amino acid substitution at aposition selected from among amino acids positions 6, 118, 269, 311,341, 350, 380, 392, 394, 433, 463, 503, 534, 535, 536, 537, 538 and 555of SEQ ID NO:2. In some embodiments, the mutation results in an ERpolypeptide having an amino acid substitution selected from among H6Y,S18P1, R269C, T311M, S341L, A350E, E380Q, V392I, R394H, S433P, S463P,R503W, V534E, P535H, L536R, L536P, L536Q, Y537N, Y537C, YS37S, D538G,and R555C. In some embodiments, the patient has two or more mutations inthe ESR1 gene.

Given the central role of ER-α in breast cancer development andprogression, compounds disclosed herein are useful in the treatment ofbreast cancer, either alone or in combination with other agent agentsthat can modulate other critical pathways in breast cancer, includingbut not limited to those that target IGF1R, EGFR, CDK 4/6, erB-B2 and 3,the PI3K/AKT/mTOR axis, HSP90, PARP or histone deacetylases.

Given the central role of ER-α in breast cancer development andprogression, Formula I compounds disclosed herein are useful in thetreatment of breast cancer, either alone or in combination with otheragent used to treat breast cancer, including but not limited toaromatase inhibitors, anthracyclines, platins, nitrogen mustardalkylating agents, taxanes. Illustrative agent used to treat breastcancer, include, but are not limited to, PI3K inhibitors such astaselisib (GDC-0032, Genentech Inc.), paclitaxel, anastrozole,exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole(FEMARA®, Novartis, Corp.), gemcitabine, trastuzumab, pegfilgrastim,filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine(XELODA®, Roche), ixabepilone, as well as others described herein.

ER-related diseases or conditions include ER-α dysfunction is associatedwith cancer (bone cancer, breast cancer, lung cancer, colorectal cancer,endometrial cancer, prostate cancer, ovarian and uterine cancer),central nervous system (CNS) defects (alcoholism, migraine),cardiovascular system defects (aortic aneurysm, susceptibility tomyocardial infarction, aortic valve sclerosis, cardiovascular disease,coronary artery disease, hypertension), hematological system defects(deep vein thrombosis), immune and inflammation diseases (Graves'Disease, arthritis, multiple sclerosis, cirrhosis), susceptibility toinfection (hepatitis B, chronic liver disease), metabolic defects (bonedensity, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia,osteoporosis), neurological defects (Alzheimer's disease, Parkinson'sdisease, migraine, vertigo), psychiatric defects (anorexia nervosa,attention deficit hyperactivity disorder (ADHD), dementia, majordepressive disorder, psychosis) and reproductive defects (age ofmenarche, endometriosis, infertility.

In some embodiments, compounds disclosed herein are used in thetreatment of an estrogen receptor dependent or estrogen receptormediated disease or condition in mammal.

In some embodiments, compounds disclosed herein are used to treat cancerin a mammal. In some embodiments, the cancer is breast cancer, ovariancancer, endometrial cancer, prostate cancer, or uterine cancer. In someembodiments, the cancer is breast cancer, lung cancer, ovarian cancer,endometrial cancer, prostate cancer, or uterine cancer. In someembodiments, the cancer is breast cancer. In some embodiments, thecancer is a hormone dependent cancer. In some embodiments, the cancer isan estrogen receptor dependent cancer. In some embodiments, the canceris an estrogen-sensitive cancer. In some embodiments, the cancer isresistant to anti-hormonal treatment. In some embodiments, the cancer isan estrogen-sensitive cancer or an estrogen receptor dependent cancerthat is resistant to anti-hormonal treatment. In some embodiments, thecancer is a hormone-sensitive cancer or a hormone receptor dependentcancer that is resistant to anti-hormonal treatment. In someembodiments, anti-hormonal treatment includes treatment with at leastone agent selected from tamoxifen, fulvestrant, steroidal aromataseinhibitors, and non-steroidal aromatase inhibitors.

In some embodiments, compounds disclosed herein are used to treathormone receptor positive metastatic breast cancer in a postmenopausalwoman with disease progression following anti-estrogen therapy.

In some embodiments, compounds disclosed herein are used to treat ahormonal dependent benign or malignant disease of the breast orreproductive tract in a mammal. In some embodiments, the benign ormalignant disease is breast cancer.

In some embodiments, the compound used in any of the methods describedherein is an estrogen receptor degrader; is an estrogen receptorantagonist; has minimal or negligible estrogen receptor agonistactivity; or combinations thereof.

In some embodiments, methods of treatment with compounds describedherein include a treatment regimen that includes administering radiationtherapy to the mammal.

In some embodiments, methods of treatment with compounds describedherein include administering the compound prior to or following surgery.

In some embodiments, methods of treatment with compounds describedherein include administering to the mammal at least one additionalanti-cancer agent.

In some embodiments, compounds disclosed herein are used to treat cancerin a mammal, wherein the mammal is chemotherapy-naïve.

In some embodiments, compounds disclosed herein are used in thetreatment of cancer in a mammal. In some embodiments, compoundsdisclosed herein are used to treat cancer in a mammal, wherein themammal is being treated for cancer with at least one anti-cancer agent.In one embodiment, the cancer is a hormone refractory cancer.

In some embodiments, compounds disclosed herein are used in thetreatment or prevention of diseases or conditions of the uterus in amammal. In some embodiments, the disease or condition of the uterus isleiomyoma, uterine leiomyoma, endometrial hyperplasia, or endometriosis.In some embodiments, the disease or condition of the uterus is acancerous disease or condition of the uterus. In some other embodiments,the disease or condition of the uterus is a non-cancerous disease orcondition of the uterus.

In some embodiments, compounds disclosed herein are used in thetreatment of endometriosis in a mammal.

In some embodiments, compounds disclosed herein are used in thetreatment of leiomyoma in a mammal. In some embodiments, the leiomyomais a uterine leiomyoma, esophageal leiomyoma, cutaneous leiomyoma, orsmall bowel leiomyoma. In some embodiments, compounds disclosed hereinare used in the treatment of fibroids in a mammal. In some embodiments,compounds disclosed herein are used in the treatment of uterine fibroidsin a mammal.

Tetrahydronaphthalene Compounds

The present invention provides tetrahydronaphthalene compounds ofFormula I, including Formulas Ia-Ij, and pharmaceutical formulationsthereof, which are potentially useful in the treatment of diseases,conditions and/or disorders modulated by Estrogen Receptor alpha (ERa).

Formula I compounds have the structure:

and stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, wherein:

Y¹ is CR^(b) or N;

Y² is —(CH₂)—, —(CH₂CH₂)—, or NR^(a);

Y³ is NR^(a) or C(R^(b))₂;

where one of Y¹, Y² and Y³ is N or NR^(a);

R^(a) and R^(c) are independently selected from H, C₁-C₆ alkyl, C₁-C₆fluoroalkyl, allyl, propargyl, C₃-C₆ cycloalkyl, and C₃-C₆ heterocyclyl,optionally substituted with one or more groups independently selectedfrom F, Cl, Br, I, CN, OH, OCH₃, and SO₂CH₃;

R^(b) is independently selected from H, —O(C₁-C₃ alkyl), C₁-C₆ alkyl,C₁-C₆ fluoroalkyl, allyl, propargyl, C₃-C₆ cycloalkyl, and C₃-C₆heterocyclyl, optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, CN, OH, OCH₃, and SO₂CH₃;

where at least one of R^(a) and R^(b) is —CH₂Cl, —CH₂F, —CHF₂, —CF₃,—CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, CH₂CH₂Cl, CH₂CH₂CH₂F, CH₂CH₂CHF₂,CH₂CH₂CF₃, or CH₂CH₂CH₂Cl;

X¹, X², X³, and X⁴ are independently selected from CH, CR⁵ and N; wherenone, one, or two of X¹, X², X³, and X⁴ is N;

Z is selected from O, S, S(O), S(O)₂, C(═O), CH(OH), C₁-C₆ alkyldiyl,CH(OH)—(C₁-C₆ alkyldiyl), C₁-C₆ fluoroalkyldiyl, NR^(c), NR^(c)—(C₁-C₆alkyldiyl), NR^(c)—(C₁-C₆ fluoroalkyldiyl), O—(C₁-C₆ alkyldiyl), andO—(C₁-C₆ fluoroalkyldiyl);

R¹ and R² are independently selected from H, F, Cl, Br, I, —CN, —CH₃,—CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH,—C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃,—CH₂OP(O)(OH)₂, —CH₂Cl, —CH₂F, —CHF₂, —CH₂NH₂, —CH₂NHSO₂CH₃, —CH₂NHCH₃,—CH₂N(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH(CH₃)CN, —C(CH₃)₂CN, —CH₂CN,—CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂, —CONHCH₃,—CONHCH₂CH₃, —CONHCH(CH₃)₂, —CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂, —NHCH₃,—N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃, —N(CH₃)C(CH₃)₂CONH₂,—N(CH₃)CH₂CH₂S(O)₂CH₃, —NO₂, ═O, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OCH₃,—OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂, —S(O)₂N(CH₃)₂, —SCH₃,—S(O)₂CH₃, —S(O)₃H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl,azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino,azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl,pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl,morpholino-methanone, and morpholino;

R³ is selected from C₃-C₂₀ cycloalkyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl,C₁-C₂₀ heteroaryl, —(C₁-C₆ alkyldiyl)-(C₃-C₂₀ cycloalkyl), —(C₁-C₆alkyldiyl)-(C₂-C₂₀ heterocyclyl), —(C₁-C₆ alkyldiyl)-(C₆-C₂₀ aryl), and—(C₁-C₆ alkyldiyl)-(C₁-C₂₀ heteroaryl);

or R³ forms a 3-6-membered spiro carbocyclic or heterocyclic group;

R⁴ and R⁵ are independently selected from F, Cl, Br, I, —CN, —CH₃,—CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH,—C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃,—CH₂OP(O)(OH)₂, —CH₂F, —CHF₂, —CH₂NH₂, —CH₂NHSO₂CH₃, —CH₂NHCH₃,—CH₂N(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH(CH₃)CN, —C(CH₃)₂CN, —CH₂CN,—CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂, —CONHCH₃,—CONHCH₂CH₃, —CONHCH(CH₃)₂, —CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂, —NHCH₃,—N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃, —N(CH₃)C(CH₃)₂CONH₂,—N(CH₃)CH₂CH₂S(O)₂CH₃, —NO₂, ═O, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OCH₃,—OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂, —S(O)₂N(CH₃)₂, —SCH₃,—S(O)₂CH₃, —S(O)₃H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl,azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino,azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl,pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl,morpholino-methanone, and morpholino; and

m is selected from 0, 1, 2, 3, and 4;

where alkyldiyl, fluoroalkyldiyl, aryl, carbocyclyl, heterocyclyl, andheteroaryl are optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, —CN, —CH₃, —CH₂CH₃, —CH(CH₃)₂,—CH₂CH(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂,—C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃, —CH₂OP(O)(OH)₂, —CH₂F, —CHF₂, —CF₃,—CH₂CF₃, —CH₂CHF₂, —CH(CH₃)CN, —C(CH₃)₂CN, —CH₂CN, —CH₂NH₂,—CH₂NHSO₂CH₃, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CO₂H, —COCH₃, —CO₂CH₃,—CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂, —CONHCH₃, —CON(CH₃)₂, —C(CH₃)₂CONH₂,—NH₂, —NHCH₃, —N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃,—N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃, —NO₂, ═O, —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂OCH₃, —OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂,—S(O)₂N(CH₃)₂, —SCH₃, —S(O)₂CH₃, —S(O)₃H, cyclopropyl, cyclopropylamide,cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy,N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl,pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl,morpholinomethyl, morpholino-methanone, and morpholino.

Formula Ia-j compounds have the structures:

wherein R⁶ is F, Cl, Br, I, —CN, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂,—CH₂OH, —CH₂OCH₃, —CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH,—CH₂CH₂SO₂CH₃, —CH₂OP(O)(OH)₂, —CH₂F, —CHF₂, —CH₂NH₂, —CH₂NHSO₂CH₃,—CH₂NHCH₃, —CH₂N(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH(CH₃)CN, —C(CH₃)₂CN,—CH₂CN, —CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂,—CONHCH₃, —CONHCH₂CH₃, —CONHCH(CH₃)₂, —CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂,—NHCH₃, —N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃,—N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃, —NO₂, ═O, —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂OCH₃, —OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂,—S(O)₂N(CH₃)₂, —SCH₃, —S(O)₂CH₃, —S(O)₃H, cyclopropyl, cyclopropylamide,oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy,N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl,pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl,morpholinomethyl, morpholino-methanone, and morpholino; and

n is selected from 0, 1, 2, 3, and 4;

wherein R^(a) is —CH₂Cl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, or—CH₂CF₃,

Exemplary embodiments of Formula I compounds include wherein R^(a) is—CH₂Cl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, or —CH₂CF₃.

Exemplary embodiments of Formula I compounds include wherein Y¹ isCR^(b) and Y³ is NR^(a).

Exemplary embodiments of Formula I compounds include wherein Y¹ is N andY³ is C(R^(b))₂.

Exemplary embodiments of Formula I compounds include wherein Y² is—(CH₂)—.

Exemplary embodiments of Formula I compounds include wherein Y² is—(CH₂CH₂)—.

Exemplary embodiments of Formula I compounds include wherein Y³ isNR^(a) and R^(a) is —CH₂Cl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, or—CH₂CF₃.

Exemplary embodiments of Formula I compounds include wherein X¹, X², X³,and X⁴ are independently selected from CH and CR⁵.

Exemplary embodiments of Formula I compounds include wherein one of X¹,X², X³, and X⁴ is N.

Exemplary embodiments of Formula I compounds include wherein Z is O orO—(C₁-C₆ alkyldiyl).

Exemplary embodiments of Formula I compounds include wherein R¹ and R²are H.

Exemplary embodiments of Formula I compounds include wherein R³ isC₆-C₂₀ aryl.

Exemplary embodiments of Formula I compounds include wherein R³ isphenyl.

Exemplary embodiments of Formula I compounds include wherein R³ isphenyl substituted with one or more F.

Exemplary embodiments of Formula I compounds include wherein R⁴ is OH,and m is 1.

Exemplary embodiments of Formula I compounds include wherein R⁵ is F andn is 2.

Exemplary embodiments of Formula I compounds include wherein R⁵ is H.

Exemplary embodiments of Formula I compounds include wherein n is 0.

Biological Evaluation

The relative efficacies of Formula I compounds as inhibitors of anenzyme activity (or other biological activity) can be established bydetermining the concentrations at which each compound inhibits theactivity to a predefined extent and then comparing the results.Typically, the preferred determination is the concentration thatinhibits 50% of the activity in a biochemical assay, i.e., the 50%inhibitory concentration or “IC₅₀”. Determination of IC₅₀ values can beaccomplished using conventional techniques known in the art. In general,an IC₅₀ can be determined by measuring the activity of a given enzyme inthe presence of a range of concentrations of the inhibitor under study.The experimentally obtained values of enzyme activity then are plottedagainst the inhibitor concentrations used. The concentration of theinhibitor that shows 50% enzyme activity (as compared to the activity inthe absence of any inhibitor) is taken as the IC₅₀ value. Analogously,other inhibitory concentrations can be defined through appropriatedeterminations of activity. For example, in some settings it can bedesirable to establish a 90% inhibitory concentration, i.e., IC₉₀, etc.

Cell proliferation, cytotoxicity, and cell viability of the Formula Icompounds can be measure by the CellTiter-Glo® Luminescent CellViability Assay (Promega Corp.). The CellTiter-Glo® Luminescent CellViability Assay is a homogeneous method of determining the number ofviable cells in culture based on quantitation of the ATP present, anindicator of metabolically active cells. The CellTiter-Glo® Assay isdesigned for use with multiwell formats, making it ideal for automatedhigh-throughput screening (HTS), cell proliferation and cytotoxicityassays. The homogeneous assay procedure involves adding the singlereagent (CellTiter-Glo® Reagent) directly to cells cultured inserum-supplemented medium. Cell washing, removal of medium and multiplepipetting steps are not required. The system detects as few as 15cells/well in a 384-well format in 10 minutes after adding reagent andmixing.

Exemplary Formula I compounds in Table 1 were made, characterized, andtested for binding to ERa (Estrogen Receptor alpha) and biologicalactivity according to the assays, protocols, and procedures of Examples901-907. ER-alpha MCF7 HCS S_(inf) (%) values in Table 1 were measuredby the Breast Cancer Cell ERa High Content Fluorescence ImagingDegradation Assay of Example 901. Anti-proliferative effects Formula Icompounds were measured by the assays described in Examples 902 and 903.The rat uterine wet weight assays of Examples 906 and 906 allow rapiddetermination of compound antagonist activity in an ER responsive tissue(immature rat uterus) while competing against the native ER ligandestradiol, i.e. antagonist mode (Ashby, J.; et al (1997) Regulatorytoxicology and pharmacology: RTP, 25 (3):226-31).

Exemplary Formula I compounds may be compared with 1-methylazetidin-3-ylcomparator compounds A and B. While A and B have potency in the ER-alphaMCF7 HCS in vitro cell proliferation assay, the degradation activitiesmeasured as ER-alpha MCF7 HCS S_(inf) (%) values are low.

Exemplary Formula I compounds may be compared with lasofoxifene(FABLYN®, Pfizer, CAS Reg. 180916-16-9, Gennari, L. et al (2006) ExpertOpin. Investig. Drugs 15 (9): 1091-103) in the MCF7 ERa degradationassay. The maximal degradation effect (S inf) of lasofoxifene is −73.5%,which is significantly lower than many of the Formula I compounds ofTable 1. Formula I compounds demonstrate surprising and unexpectedcell-based potency and efficient ERa degradation.

Exemplary Formula I compounds in Tables 1a and 1b have the followingstructures, corresponding names (ChemBioDraw, Versions 11, 12, or 14,CambridgeSoft Corp., Cambridge Mass.), and biological activity. Wheremore than one name is associated with a Formula I compound orintermediate, the chemical structure shall define the compound.Assignment of configuration at chiral centers may be tentative. Theinvention contemplates all stereoisomers, as racemic mixtures,stereoisomeric enriched mixtures, separated enantiomers ordiastereomers.

TABLE 1a ER-alpha ER- (WT) alpha MCF7 (WT) HCS MCF7 Mass (EC50) HCSSpec. No. Structure IUPAC Name (μMol) (S inf) M + H/1 101

(1R,2S)-1-[4-[2-[3- (fluoromethyl)azetidin- 1-yl]ethoxy]phenyl]-2-phenyl-tetralin-6-ol 0.000371 −100 432.2 102

(1S,2R)-1-[4-[2-[3- (fluoromethyl)azetidin- 1-yl]ethoxy]phenyl]-2-phenyl-tetralin-6-ol 0.00812 −94.7 432.2 103

(1S,2R)-1-[4-[2-[3- (fluoromethyl)azetidin- 1-yl]ethoxy]phenyl]- 2-(4-fluorophenyl)tetralin- 6-ol 0.0386 −78 450.1 104

(1R,2R)-1-[2,6- difluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]- 2-phenyl-tetralin-6-ol 0.0156 −95 468.2 105

(1S,2S)-1-[2,6- difluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]- 2-phenyl-tetralin-6-ol 0.0000404 −98.7 468.2 106

(1R,2S)-1-[4-[2-[3- (fluoromethyl)azetidin- 1-yl]ethoxy]phenyl]- 2-(4-fluorophenyl)tetralin- 6-ol 0.000977 −97 450.1 107

(5R,6R)-5-(4-(2-(3- (fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)-6-(tetrahydro-2H- pyran-4-yl)-5,6,7,8- tetrahydronaphthalen- 2-ol 0.0164−87.8 440.3 108

(5S,6S)-6-(4,4- difluorocyclohexyl)-5- (4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)- 5,6,7,8- tetrahydronaphthalen- 2-ol 0.0146 −97474.3 109

(5S,6S)-5-(4-(2-(3- (fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)-6-(tetrahydro-2H- pyran-4-yl)-5,6,7,8- tetrahydronaphthalen- 2-ol0.000164 −95.2 440.4 110

(5R,6R)-6-(4,4- difluorocyclohexyl)-5- (4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)- 5,6,7,8- tetrahydronaphthalen- 2-ol 0.000177 −98.2474.3 111

(5R,6S)-5-(4-(2-(3- (fluoromethyl)pyrrolidin- 1- yl)ethoxy)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.047 −55 446.3 112

(5R,6S)-5-(4-(2-(3- (chloromethyl)azetidin- 1-yl)ethoxy)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.0509 −35 448.2 113

(5S,6R)-5-(4-(2-(3- (chloromethyl)azetidin- 1-yl)ethoxy)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.000177 −93.6 448.2 114

(5S,6R)-5-(4-(2-(3- (fluoromethyl)pyrrolidin- 1- yl)ethoxy)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.00010 −94.2 446.2 115

(5S,6R)-5-(4-(2-(3- (fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)- 6-(4-(methylsulfonyl)phenyl)- 5,6,7,8- tetrahydronaphthalen- 2-ol 0.0394 −75510.2 116

(5S,6R)-5-(4-(2-(3- (difluoromethyl)azetidin- 1- yl)ethoxy)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol >0.10 450.2 117

(5R,6S)-5-(4-(2-(3- (fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)- 6-(4-(methylsulfonyl)phenyl)- 5,6,7,8- tetrahydronaphthalen- 2-ol 0.000227−91.4 510.2 118

(5R,6S)-5-(4-(2-(3- (difluoromethyl)azetidin- 1- yl)ethoxy)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.000184 −93.6 450.3 119

(5R,6R)-5-(2-fluoro-4- (2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)- 6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.0165−85 450.2 120

(5S,6S)-5-(2-fluoro-4- (2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)- 6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol0.000036 −98.8 450.2 121

(S)-1′-(4-(2-(3- (fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)-3′,4′-dihydro-1′H- spiro[cyclopentane- 1,2′-naphthalen]-6′-ol 0.000208−98.5 410.2 122

(R)-1′-(4-(2-(3- (fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)-3′,4′-dihydro-1′H- spiro[cyclopentane- 1,2′-naphthalen]-6′-ol 0.000451−99.2 410.2 123

(5R,6S)-5-(4-((S)-2- ((R)-3- (fluoromethyl)pyrrolidin- 1-yl)propoxy)phenyl)-6- phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.0169−30 460.4 124

(5S,6R)-5-(4-((S)-2- ((R)-3- (fluoromethyl)pyrrolidin- 1-yl)propoxy)phenyl)-6- phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol0.0000371 −93.4 460.3 125

(5R,6S)-5-(4-(((R)-1- ((R)-3- (fluoromethyl)pyrrolidin- 1-yl)propan-2-yl)oxy)phenyl)-6- phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol >0.10 460.3126

(5S,6R)-5-(4-(((R)-1- ((R)-3- (fluoromethyl)pyrrolidin- 1-yl)propan-2-yl)oxy)phenyl)-6- phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.000675−97.1 460.3 127

(5S,6S)-5-(6-(2-(3- (fluoromethyl)azetidin- 1-yl)ethoxy)pyridin-3-yl)-6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.0000461 −96.5 433.2128

(5R,6R)-5-(6-(2-(3- (fluoromethyl)azetidin- 1-yl)ethoxy)pyridin-3-yl)-6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.0125 −84 433.2 129

(5S,6R)-5-(4-((1-(3- fluoropropyl)azetidin- 3-yl)oxy)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol >0.10 432.2 130

(5R,6S)-5-(4-((1-(3- fluoropropyl)azetidin- 3-yl)oxy)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.000107 −99.3 432.2 131

(5S,6R)-5-(4-((1-(3- fluoropropyl)azetidin- 3-yl)amino)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.0138 −35 431.2 132

(5R,6S)-5-(4-((1-(3- fluoropropyl)azetidin- 3-yl)amino)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.000029 −99.9 431.2

TABLE 1b ER-alpha ER- (WT) alpha MCF7 (WT) HCS MCF7 Mass (EC50) HCSSpec. No. Structure IUPAC Name (μMol) (S inf) M + H/1 133

4-((1R,2S)-1-(4-(2-(3- (fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)-6-hydroxy-1,2,3,4- tetrahydronaphthalen- 2-yl)benzonitrile 0.053 −30457.2 134

4-((1S,2R)-1-(4-(2-(3- (fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)-6-hydroxy-1,2,3,4- tetrahydronaphthalen- 2-yl)benzonitrile 0.0000385−99.2 457.2 135

(7S,8R)-8-(4-(2-(3- (fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)-7-phenyl-5,6,7,8- tetrahydronaphthalen- 1-ol 0.0298 −82 432.2 136

(7R,8S)-8-(4-(2-(3- (fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)-7-phenyl-5,6,7,8- tetrahydronaphthalen- 1-ol 0.186 −80 432.2 137

(5R,6S)-5-(4-((2-(3- (fluoromethyl)azetidin- 1- yl)ethyl)amino)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.186 −80 431.2 138

(5S,6R)-5-(4-((2-(3- (fluoromethyl)azetidin- 1- yl)ethyl)amino)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol 0.000203 −89.89 431.2 139

(5R,6S)-5-(4-((2-((R)- 3- (fluoromethyl)pyrrolidin- 1-yl)ethyl)amino)phenyl)- 6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol0.228 −50 445.26 140

(5S,6R)-5-(4-((2-((R)- 3- (fluoromethyl)pyrrolidin- 1-yl)ethyl)amino)phenyl)- 6-phenyl-5,6,7,8- tetrahydronaphthalen- 2-ol0.000773 −45 445.26

Comparator Compounds A, B, and Lasofoxifene

A

(5R,6S)-5-(4-(2-(1- methylazetidin-3- yl)ethoxy)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen-2- ol 0.019 −58 414.24 B

(5S,6R)-5-(4-(2-(1- methylazetidin-3- yl)ethoxy)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen-2- ol 0.000026 −43.35 414.24lasofoxifene

(5R,6S)-6-phenyl-5- (4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)- 5,6,7,8-tetrahydronaphthalen- 2-ol 0.000054 −73.5 414.24Administration of Formula I Compounds

The compounds of the invention may be administered by any routeappropriate to the condition to be treated. Suitable routes includeoral, parenteral (including subcutaneous, intramuscular, intravenous,intraarterial, intradermal, intrathecal and epidural), transdermal,rectal, nasal, topical (including buccal and sublingual), vaginal,intraperitoneal, intrapulmonary and intranasal. For localimmunosuppressive treatment, the compounds may be administered byintralesional administration, including perfusing or otherwisecontacting the graft with the inhibitor before transplantation. It willbe appreciated that the preferred route may vary with for example thecondition of the recipient. Where the compound is administered orally,it may be formulated as a pill, capsule, tablet, etc. with apharmaceutically acceptable carrier or excipient. Where the compound isadministered parenterally, it may be formulated with a pharmaceuticallyacceptable parenteral vehicle and in a unit dosage injectable form, asdetailed below.

A dose to treat human patients may range from about 10 mg to about 1000mg of Formula I compound. A typical dose may be about 100 mg to about300 mg of the compound. A dose may be administered once a day (QID),twice per day (BID), or more frequently, depending on thepharmacokinetic and pharmacodynamic properties, including absorption,distribution, metabolism, and excretion of the particular compound. Inaddition, toxicity factors may influence the dosage and administrationregimen. When administered orally, the pill, capsule, or tablet may beingested daily or less frequently for a specified period of time. Theregimen may be repeated for a number of cycles of therapy.

Methods of Treatment with Formula I Compounds

Formula I compounds of the present invention are useful for treating ahuman or animal patient suffering from a disease or disorder arisingfrom abnormal cell growth, function or behavior associated with USP7such as an immune disorder, cardiovascular disease, viral infection,inflammation, a metabolism/endocrine disorder or a neurologicaldisorder, may thus be treated by a method comprising the administrationthereto of a compound of the present invention as defined above. A humanor animal patient suffering from cancer may also be treated by a methodcomprising the administration thereto of a compound of the presentinvention as defined above. The condition of the patient may thereby beimproved or ameliorated.

Methods of the invention also include treating cancer selected frombreast, ovary, cervix, prostate, testis, genitourinary tract, esophagus,larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma,lung, epidermoid carcinoma, large cell carcinoma, non-small cell lungcarcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone,colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, pancreatic, myeloid disorders, lymphoma, hairy cells, buccalcavity, naso-pharyngeal, pharynx, lip, tongue, mouth, small intestine,colon-rectum, large intestine, rectum, brain and central nervous system,Hodgkin's, leukemia, bronchus, thyroid, liver and intrahepatic bileduct, hepatocellular, gastric, glioma/glioblastoma, endometrial,melanoma, kidney and renal pelvis, urinary bladder, uterine corpus,uterine cervix, multiple myeloma, acute myelogenous leukemia, chronicmyelogenous leukemia, lymphocytic leukemia, chronic lymphoid leukemia(CLL), myeloid leukemia, oral cavity and pharynx, non-Hodgkin lymphoma,melanoma, and villous colon adenoma.

Pharmaceutical Formulations

In order to use a compound of this invention for the therapeutictreatment of mammals including humans, it is normally formulated inaccordance with standard pharmaceutical practice as a pharmaceuticalcomposition. According to this aspect of the invention there is provideda pharmaceutical composition comprising a compound of this invention inassociation with a pharmaceutically acceptable diluent or carrier.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. Suitable carriers,diluents and excipients are well known to those skilled in the art andinclude materials such as carbohydrates, waxes, water soluble and/orswellable polymers, hydrophilic or hydrophobic materials, gelatin, oils,solvents, water and the like. The particular carrier, diluent orexcipient used will depend upon the means and purpose for which thecompound of the present invention is being applied. Solvents aregenerally selected based on solvents recognized by persons skilled inthe art as safe (GRAS) to be administered to a mammal. In general, safesolvents are non-toxic aqueous solvents such as water and othernon-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the compound (e.g.,complex with a cyclodextrin derivative or other known complexationagent) is dissolved in a suitable solvent in the presence of one or moreof the excipients described above. The compound of the present inventionis typically formulated into pharmaceutical dosage forms to provide aneasily controllable dosage of the drug and to enable patient compliancewith the prescribed regimen.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

Pharmaceutical formulations of the compounds of the present inventionmay be prepared for various routes and types of administration. Forexample, a compound of Formula I having the desired degree of purity mayoptionally be mixed with pharmaceutically acceptable diluents, carriers,excipients or stabilizers (Remington's Pharmaceutical Sciences (1980)16th edition, Osol, A. Ed.), in the form of a lyophilized formulation,milled powder, or an aqueous solution. Formulation may be conducted bymixing at ambient temperature at the appropriate pH, and at the desireddegree of purity, with physiologically acceptable carriers, i.e.,carriers that are non-toxic to recipients at the dosages andconcentrations employed. The pH of the formulation depends mainly on theparticular use and the concentration of compound, but may range fromabout 3 to about 8. Formulation in an acetate buffer at pH 5 is asuitable embodiment.

The compound ordinarily can be stored as a solid composition, alyophilized formulation or as an aqueous solution.

The pharmaceutical compositions of the invention will be formulated,dosed and administered in a fashion, i.e., amounts, concentrations,schedules, course, vehicles and route of administration, consistent withgood medical practice. Factors for consideration in this context includethe particular disorder being treated, the particular mammal beingtreated, the clinical condition of the individual patient, the cause ofthe disorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners. The “therapeutically effective amount”of the compound to be administered will be governed by suchconsiderations, and is the minimum amount necessary to ameliorate, ortreat the hyperproliferative disorder.

As a general proposition, the initial pharmaceutically effective amountof the inhibitor administered parenterally per dose will be in the rangeof about 0.01-100 mg/kg, namely about 0.1 to 20 mg/kg of patient bodyweight per day, with the typical initial range of compound used being0.3 to 15 mg/kg/day.

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Theactive pharmaceutical ingredients may also be entrapped in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations of compounds of Formula I may beprepared. Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of Formula I, which matrices are in the form of shapedarticles, e.g., films, or microcapsules. Examples of sustained-releasematrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid.The formulations include those suitable for the administration routesdetailed herein. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).Such methods include the step of bringing into association the activeingredient with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product.

Formulations of a compound of Formula I suitable for oral administrationmay be prepared as discrete units such as pills, capsules, cachets ortablets each containing a predetermined amount of a compound of FormulaI. Compressed tablets may be prepared by compressing in a suitablemachine the active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs may be prepared for oral use. Formulationsof compounds of Formula I intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a palatablepreparation. Tablets containing the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipient which are suitable formanufacture of tablets are acceptable. These excipients may be, forexample, inert diluents, such as calcium or sodium carbonate, lactose,calcium or sodium phosphate; granulating and disintegrating agents, suchas maize starch, or alginic acid; binding agents, such as starch,gelatin or acacia; and lubricating agents, such as magnesium stearate,stearic acid or talc. Tablets may be uncoated or may be coated by knowntechniques including microencapsulation to delay disintegration andadsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate alone or with a wax may beemployed.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientsmay be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients may be formulated in a creamwith an oil-in-water cream base. If desired, the aqueous phase of thecream base may include a polyhydric alcohol, i.e., an alcohol having twoor more hydroxyl groups such as propylene glycol, butane 1,3-diol,mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400)and mixtures thereof. The topical formulations may desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethyl sulfoxide and relatedanalogs. The oily phase of the emulsions of this invention may beconstituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it desirably comprises a mixture ofat least one emulsifier with a fat or an oil or with both a fat and anoil. Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

Aqueous suspensions of Formula I compounds contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, croscarmellose, povidone, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth and gum acacia, and dispersing or wetting agents such asa naturally occurring phosphatide (e.g., lecithin), a condensationproduct of an alkylene oxide with a fatty acid (e.g., polyoxyethylenestearate), a condensation product of ethylene oxide with a long chainaliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension may also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

The pharmaceutical compositions of compounds of Formula I may be in theform of a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butanediol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis disorders as described below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

The formulations may be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefore. Veterinary carriers are materials useful for thepurpose of administering the composition and may be solid, liquid orgaseous materials which are otherwise inert or acceptable in theveterinary art and are compatible with the active ingredient. Theseveterinary compositions may be administered parenterally, orally or byany other desired route.

Combination Therapy

The compounds of Formula I may be employed alone or in combination withadditional therapeutic agents for the treatment of a disease or disorderdescribed herein, such as inflammation or a hyperproliferative disorder(e.g., cancer). In certain embodiments, a compound of Formula I iscombined in a pharmaceutical combination formulation, or dosing regimenas combination therapy, with an additional, second therapeutic compoundthat has anti-inflammatory or anti-hyperproliferative properties or thatis useful for treating an inflammation, immune-response disorder, orhyperproliferative disorder (e.g., cancer). The additional therapeuticmay be a Bcl-2 inhibitor, a JAK inhibitor, a PI3K inhibitor, an mTORinhibitor, an anti-inflammatory agent, an immunomodulatory agent,chemotherapeutic agent, an apoptosis-enhancer, a neurotropic factor, anagent for treating cardiovascular disease, an agent for treating liverdisease, an anti-viral agent, an agent for treating blood disorders, anagent for treating diabetes, and an agent for treating immunodeficiencydisorders. The second therapeutic agent may be an NSAIDanti-inflammatory agent. The second therapeutic agent may be achemotherapeutic agent. The second compound of the pharmaceuticalcombination formulation or dosing regimen preferably has complementaryactivities to the compound of Formula I such that they do not adverselyaffect each other. Such compounds are suitably present in combination inamounts that are effective for the purpose intended. In one embodiment,a composition of this invention comprises a compound of Formula I, or astereoisomer, tautomer, solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof, in combination with a therapeuticagent such as an NSAID.

The combination therapy may be administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations. The combinedadministration includes coadministration, using separate formulations ora single pharmaceutical formulation, and consecutive administration ineither order, wherein preferably there is a time period while both (orall) active agents simultaneously exert their biological activities.

Suitable dosages for any of the above coadministered agents are thosepresently used and may be lowered due to the combined action (synergy)of the newly identified agent and other therapeutic agents ortreatments.

The combination therapy may provide “synergy” and prove “synergistic”,i.e., the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect may be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes,separate pills or capsules, or separate infusions. In general, duringalternation therapy, an effective dosage of each active ingredient isadministered sequentially, i.e., serially, whereas in combinationtherapy, effective dosages of two or more active ingredients areadministered together.

In a particular embodiment of therapy, a compound of Formula I, or astereoisomer, tautomer, solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof, may be combined with othertherapeutic, hormonal or antibody agents such as those described herein,as well as combined with surgical therapy and radiotherapy. Combinationtherapies according to the present invention thus comprise theadministration of at least one compound of Formula I, or a stereoisomer,tautomer, solvate, metabolite, or pharmaceutically acceptable salt orprodrug thereof, and the use of at least one other cancer treatmentmethod. The amounts of the compound(s) of Formula I and the otherpharmaceutically active therapeutic agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect.

Metabolites of Compounds of Formula I

Also falling within the scope of this invention are the in vivometabolic products of Formula I described herein. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,deamidation, esterification, deesterification, enzymatic cleavage, andthe like, of the administered compound. Accordingly, the inventionincludes metabolites of compounds of Formula I, including compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Articles of Manufacture

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the diseases anddisorders described above is provided. In one embodiment, the kitcomprises a container comprising a compound of Formula I, or astereoisomer, tautomer, solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof. The kit may further comprise a labelor package insert on or associated with the container. The term “packageinsert” is used to refer to instructions customarily included incommercial packages of therapeutic products, that contain informationabout the indications, usage, dosage, administration, contraindicationsand/or warnings concerning the use of such therapeutic products.Suitable containers include, for example, bottles, vials, syringes,blister pack, etc. The container may be formed from a variety ofmaterials such as glass or plastic. The container may hold a compound ofFormula I or a formulation thereof which is effective for treating thecondition and may have a sterile access port (for example, the containermay be an intravenous solution bag or a vial having a stopper pierceableby a hypodermic injection needle). At least one active agent in thecomposition is a compound of Formula I. The label or package insertindicates that the composition is used for treating the condition ofchoice, such as cancer. In addition, the label or package insert mayindicate that the patient to be treated is one having a disorder such asa hyperproliferative disorder, neurodegeneration, cardiac hypertrophy,pain, migraine or a neurotraumatic disease or event. In one embodiment,the label or package inserts indicates that the composition comprising acompound of Formula I can be used to treat a disorder resulting fromabnormal cell growth. The label or package insert may also indicate thatthe composition can be used to treat other disorders. Alternatively, oradditionally, the article of manufacture may further comprise a secondcontainer comprising a pharmaceutically acceptable buffer, such asbacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.

The kit may further comprise directions for the administration of thecompound of Formula I and, if present, the second pharmaceuticalformulation. For example, if the kit comprises a first compositioncomprising a compound of Formula I and a second pharmaceuticalformulation, the kit may further comprise directions for thesimultaneous, sequential or separate administration of the first andsecond pharmaceutical compositions to a patient in need thereof.

In another embodiment, the kits are suitable for the delivery of solidoral forms of a compound of Formula I, such as tablets or capsules. Sucha kit preferably includes a number of unit dosages. Such kits caninclude a card having the dosages oriented in the order of theirintended use. An example of such a kit is a “blister pack”. Blisterpacks are well known in the packaging industry and are widely used forpackaging pharmaceutical unit dosage forms. If desired, a memory aid canbe provided, for example in the form of numbers, letters, or othermarkings or with a calendar insert, designating the days in thetreatment schedule in which the dosages can be administered.

According to one embodiment, a kit may comprise (a) a first containerwith a compound of Formula I contained therein; and optionally (b) asecond container with a second pharmaceutical formulation containedtherein, wherein the second pharmaceutical formulation comprises asecond compound with anti-hyperproliferative activity. Alternatively, oradditionally, the kit may further comprise a third container comprisinga pharmaceutically-acceptable buffer, such as bacteriostatic water forinjection (BWFI), phosphate-buffered saline, Ringer's solution anddextrose solution. It may further include other materials desirable froma commercial and user standpoint, including other buffers, diluents,filters, needles, and syringes.

In certain other embodiments wherein the kit comprises a composition ofFormula I and a second therapeutic agent, the kit may comprise acontainer for containing the separate compositions such as a dividedbottle or a divided foil packet, however, the separate compositions mayalso be contained within a single, undivided container. Typically, thekit comprises directions for the administration of the separatecomponents. The kit form is particularly advantageous when the separatecomponents are preferably administered in different dosage forms (e.g.,oral and parenteral), are administered at different dosage intervals, orwhen titration of the individual components of the combination isdesired by the prescribing physician.

Preparation of Formula I Compounds

Compounds of Formula I may be synthesized by synthetic routes thatinclude processes analogous to those well-known in the chemical arts,particularly in light of the description contained herein, and those fortetrahydronaphthalene compounds described in Bencze, W. L. et al (1967)J. Med. Chem. 10:138-144; Lednicer, D. et al (1969) J. Med. Chem.12:881-885; Prakash, C. et al (2008) 36:1218-1226; Rosati, R. L, et al(1998) J. Med. Chem. 41:2928-2931; WO 1996/021656, and otherheterocycles described in: Comprehensive Heterocyclic Chemistry II,Editors Katritzky and Rees, Elsevier, 1997, e.g. Volume 3; LiebigsAnnalen der Chemie, (9):1910-16, (1985); Helvetica Chimica Acta,41:1052-60, (1958); Arzneimittel-Forschung, 40(12): 1328-31, (1990),each of which are expressly incorporated by reference. Startingmaterials are generally available from commercial sources such asAldrich Chemicals (Milwaukee, Wis.) or are readily prepared usingmethods well known to those skilled in the art (e.g., prepared bymethods generally described in Louis F. Fieser and Mary Fieser, Reagentsfor Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), orBeilsteins Handbuch der organischen Chemie, 4, Aufl. ed.Springer-Verlag, Berlin, including supplements (also available via theBeilstein online database).

Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing Formula I compoundsand necessary reagents and intermediates are known in the art andinclude, for example, those described in R. Larock, ComprehensiveOrganic Transformations, VCH Publishers (1989); T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wileyand Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995) and subsequent editionsthereof.

Compounds of Formula I may be prepared singly or as compound librariescomprising at least 2, for example 5 to 1,000 compounds, or 10 to 100compounds. Libraries of compounds of Formula I may be prepared by acombinatorial ‘split and mix’ approach or by multiple parallel synthesesusing either solution phase or solid phase chemistry, by proceduresknown to those skilled in the art. Thus according to a further aspect ofthe invention there is provided a compound library comprising at least 2compounds, or pharmaceutically acceptable salts thereof.

The Examples provide exemplary methods for preparing Formula Icompounds.

Those skilled in the art will appreciate that other synthetic routes maybe used to synthesize the Formula I compounds. Although specificstarting materials and reagents are depicted and discussed in theFigures and Examples, other starting materials and reagents can beeasily substituted to provide a variety of derivatives and/or reactionconditions. In addition, many of the exemplary compounds prepared by thedescribed methods can be further modified in light of this disclosureusing conventional chemistry well known to those skilled in the art.

In preparing compounds of Formulas I, protection of remote functionality(e.g., primary or secondary amine) of intermediates may be necessary.The need for such protection will vary depending on the nature of theremote functionality and the conditions of the preparation methods.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection isreadily determined by one skilled in the art. For a general descriptionof protecting groups and their use, see T. W. Greene, Protective Groupsin Organic Synthesis, John Wiley & Sons, New York, 1991.

In the methods of preparing Formula I compounds, it may be advantageousto separate reaction products from one another and/or from startingmaterials. The desired products of each step or series of steps isseparated and/or purified to the desired degree of homogeneity by thetechniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like. Selection of appropriate methodsof separation depends on the nature of the materials involved, such as,boiling point and molecular weight in distillation and sublimation,presence or absence of polar functional groups in chromatography,stability of materials in acidic and basic media in multiphaseextraction, and the like.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. “Stereochemistry of OrganicCompounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,(1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: “DrugStereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem.(1982) 47:4165), of the racemic mixture, and analyzing the ¹H NMRspectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111). By method (3), a racemic mixture of two enantiomers canbe separated by chromatography using a chiral stationary phase (“ChiralLiquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, NewYork; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

Formula I compounds can be prepared by the General Procedures of Schemes1-4.

Scheme 1 shows the general synthesis of compounds 1k and 1l from atetralone, such as 6-methoxy-3,4-dihydronaphthalen-1(2H)-one 1a.Alpha-arylation reaction of a phenyl bromide 1b with ketone 1a gave 1c.Formation of the triflate and Suzuki reaction with a boronic acid 1dgave 1e. Hydrogenation to give a racemic mixture of enantiomers 1f and1g followed procedures from Lednicer, D. et al (1969) J. Med. Chem.12:881-885. Mitsunobu reaction of 1f and 1g with azetinyl orpyrrolidinyl alcohol 1h gave a racemic mixture of enantiomers 1i and 1j.Demethylation with boron tribromide gave a racemic mixture ofenantiomers 1k and 1l. Enantiomers 1k and 1l can be separated byconventional chiral separation methods such as SFC chromatography.

Scheme 2 shows the general synthesis of compounds 2n and 2o from atetralone, such as 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one 2a.Synthesis of enantiomers 2n and 2o follow procedures from Lednicer, D.et al (1969) J. Med. Chem. 12:881-885. Silyl protection of phenol groupin 2a with a trialkylsilyl chloride reagent such as triisopropylsilylchloride gave 2b, which was transformed to vinyl triflate 2c withtriflic anhydride. Suzuki coupling of 2c with an optionally substituted(R⁵) 4-hydroxyphenyl boronic acid 2d produced 2e. Alkylation of phenolin 2e 1,2-dibromoethane, followed by vinyl bromination of 2f yieldedbromide 2g. Coupling of vinyl bromide with an optionally substituted(R⁶)phenyl boronic acid gave 2h, which upon hydrogenation led tocis-tetrahydronaphthalene enantiomers 2i and 2j. Displacement of bromidewith an pyrrolidinyl or azetidinyl compound 2k where Y² is CH₂ or CH₂CH₂and Y³ is NR^(a) or C(R^(b))₂, gave 2l and 2m which were deprotected togive 2n and 2o. Enantiomers 2n and 2o can be separated by conventionalchiral separation methods such as SFC chromatography.

Scheme 3 shows the general synthesis of enantiomers 3l and 3m from atetralone, such as 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one 2a.Synthesis of enantiomers 31 and 3m follow procedures from Lednicer, D.et al (1969) J. Med. Chem. 12:881-885. Starting with tetralone 2a,protection of the phenol group with benzyl bromide and potassiumcarbonate in acetonitrile gave6-(benzyloxy)-3,4-dihydronaphthalen-1(2H)-one 3a which was converted to6-(benzyloxy)-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate 3b.Suzuki coupling of 3b with a boronic acid 3c or boronate ester produced3d. Bromination of 3d gave 3e, and followed by another Suzuki couplingreaction gave 3f. Alkylation of the phenol in 3f with tert-butyl3-iodoazetidine-1-carboxylate gave 3g, and followed by hydrogenationproduced a racemic mixture of enantiomers 3h and 3i. Removal of Bocprotecting group, followed by selective N-alkylation with an alkylationagent such as 1-fluoro-3-iodopropane gave a racemic mixture ofenantiomers 31 and 3m. Enantiomers 31 and 3m can be separated byconventional chiral separation methods such as SFC chromatography.

Scheme 4 shows the general synthesis of enantiomers 4m and 4n fromSuzuki reaction of 4-nitrophenyl boronic acid 4a and6-((triisopropylsilyl)oxy)-3,4-dihydronaphthalen-1-yltrifluoromethanesulfonate 101h. Alternatively a boronate ester of 4a canbe used. Olefin bromination of 4b gave 4c. Suzuki coupling gave 4d.Reduction of the nitro group and double bond of 4d gave a racemicmixture of enantiomers 4e and 4f. Reductive amination with tert-butyl3-oxoazetidine-1-carboxylate led to a racemic mixture of enantiomers 4gand 4h. Boc-deprotection with acid gave a racemic mixture of enantiomers4i and 4j. N-alkylation with an alkylation agent such as1-fluoro-3-iodopropane provided a racemic mixture of enantiomers 4k and4l. Finally, removal of silyl protecting group through treatment oftetrabutylammonium fluoride (TBAF) gave a racemic mixture of enantiomers4m and 4n. Enantiomers 4m and 4n can be separated by conventional chiralseparation methods such as SFC chromatography.

EXAMPLES Example 101(1R,2S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-phenyl-tetralin-6-ol101

4-((1R,2S)-6-Methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenol101d was prepared according to Lednicer D., et al (1969) J. Med. Chem.12:881-885 by alpha-arylation of6-methoxy-3,4-dihydronaphthalen-1(2H)-one 101a with phenyl bromide andpalladium catalysis to give6-methoxy-2-phenyl-3,4-dihydronaphthalen-1(2H)-one 101b. Formation ofthe enol triflate of 101b with triflic anhydride followed by couplingwith (4-hydroxyphenyl)boronic acid gave4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol 101c. Hydrogenreduction of 101c with palladium on carbon gave the cis 101d, also knownas 4-(cis-6-methoxy-2-phenyl-tetralin-1-yl)phenol.

Mitsunobu reaction of cis 101d with2-(3-(fluoromethyl)azetidin-1-yl)ethan-1-ol produced racemic3-(fluoromethyl)-1-(2-(4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy)ethyl)azetidine101e, which upon demethylation and chiral SFC separation gaveenantiomers 101 and 102.

Step A: To a solution of 4-(cis-6-methoxy-2-phenyl-tetralin-1-yl)phenol101d (75.0 mg, 0.23 mmol, prepared according to procedures in LednicerD., et al (1969) J. Med. Chem. 12:881-885, in toluene (5 mL) was added2-(3-(fluoromethyl)azetidin-1-yl)ethan-1-ol (60 mg, 0.45 mmol) andtriphenylphosphine (179 mg, 0.68 mmol). The reaction mixture was purgedwith nitrogen atmosphere for 2 min and then diisopropyl azodicarboxylate(138 mg, 0.68 mmol) was added dropwise at 0° C. The reaction was stirredat 100° C. for 16 h. After cooling to room temperature, the mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluted with 0-10% MeOH in DCM) to give 101e(a mixture of cis-enantiomers, 64 mg, 63%) as a yellow oil. LCMS: 446.1[M+H]⁺.

Step B: To a solution of 101e (a mixture of cis-enantiomers, 40.0 mg,0.090 mmol) in DCM (3 mL) was added boron tribromide (1M in DCM, 0.18mL, 0.18 mmol) dropwise at −40° C. The reaction was stirred at −40° C.for 5 h. The reaction was quenched with saturated aqueous sodiumbicarbonate (5 mL) and extracted with dichloromethane (5 mL×2). Theorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byreverse-phase HPLC (acetonitrile 50-80%/0.1% NH₄HCO₃ in water) to give101 and 102 as a mixture of cis-enantiomers (2.7 mg, 4%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.19-7.10 (m, 3H), 6.80 (d, J=7.6Hz, 2H), 6.70-6.65 (m, 2H), 6.52 (d, J=8.4 Hz, 3H), 6.31 (d, J=8.4 Hz,2H), 4.53-4.42 (m, 2H), 4.20 (m, 1H), 3.89 (t, J=5.2 Hz, 2H), 3.58 (t,J=8.0 Hz, 2H), 3.28-3.25 (m, 3H), 3.03-2.87 (m, 5H), 2.26-2.18 (m, 1H),1.77-1.75 (m, 1H). LCMS: 431.9 [M+H]⁺.

Step C: The cis-mixture was further separated by chiral SFC(supercritical fluid chromatography) to separate 101 and 102: chiral SFCconditions: AY column, 250 mm×30 mm, 10 m; supercritical CO₂/EtOH (0.1%NH₃.H₂O)=35%, flow rate=80 ml/min, example 102: Rt=4.84 min; 101:Rt=6.36 min.

Alternatively, compounds 101 and 102 can be made by the followingsynthetic route:

Step 1: 6-((Triisopropylsilyl)oxy)-3,4-dihydronaphthalen-1(2H)-one 101g

To a mixture of 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one 101f (50 g,308 mmol) and imidazole (42 g, 616 mmol) in DCM (500 mL) was addedTIPSCl (71 g, 370 mmol) dropwise at 0° C. and the reaction mixture waswarmed up to room temperature and the stirring continued for 3 hours.The mixture was diluted with DCM (800 mL), washed with water (400 mL×3)and two layers were separated. The organic layer was dried over Na₂SO₄,filtered and concentrated to afford 101g (95 g, 97% yield) as brown oil.¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, J=8.4 Hz, 1H), 6.76 (dd, J=8.4, 2.0Hz, 1H), 6.67 (d, J=2.0 Hz, 1H), 2.87 (t, J=6.0 Hz, 2H), 2.63-2.54 (m,2H), 2.10-2.07 (m, 2H), 1.33-1.20 (m, 3H), 1.09 (d, J=7.6 Hz, 18H).

Step 2: 6-((Triisopropylsilyl)oxy)-3,4-dihydronaphthalen-1-yltrifluoromethanesulfonate 101h

A solution 101g (95 g, 298 mmol) in THF (150 mL) was cooled to −78° C.and a solution of LiHMDS (1M in THF, 447 mL, 447 mmol) was addeddropwise. After stirring for 1 hour,N-phenylbis(trifluoromethanesulfonimide) (160 g, 447 mmol) was added inone portion and the reaction mixture was allowed to warm to 15° C. andstirred for 2 hours. The reaction mixture was diluted with water (1 L),extracted with DCM (1 L×2) and two layers were separated. The combinedorganic layers were washed with water (800 mL×3), dried over Na₂SO₄. Thecrude product was filtered and concentrated which was purified by columneluted with 0-9% EtOAc in petroleum ether to give 101h (110 g, 82%) aslight yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.19 (d, J=8.0 Hz, 1H),6.78-6.67 (m, 2H), 5.85 (t, J=4.8 Hz, 1H), 2.85-2.75 (m, 2H), 2.48 (m,2H), 1.33-1.21 (m, 3H), 1.11 (d, J=7.2 Hz, 18H).

Step 3: 4-(6-((Triisopropylsilyl)oxy)-3,4-dihydronaphthalen-1-yl)phenol101i

A mixture of 101h (80 g, 178 mmol), Pd(PPh₃)₄(20.5 g, 17.75 mmol) andNa₂CO₃ (56 g, 533 mmol) and 4-hydroxyphenylboronic acid (37 g, 266 mmol)in 1,4-dioxane (700 mL) and water (120 mL) was stirred at 80° C. underN₂ atmosphere for 12 hours. After cooling to room temperature, thereaction mixture was diluted with water (500 mL), extracted with DCM (1L×2) and two layers were separated. The combined organic layers weredried over Na₂SO₄, filtered, concentrated and the residue was purifiedby column chromatography on silica eluted with 0-10% EtOAc in petroleumether to afford 101i (68 g, 97%) as a yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 7.22 (d, J=8.4 Hz, 2H), 6.89-6.80 (m, 3H), 6.72 (d, J=2.0 Hz,1H), 6.60 (dd, J=8.4, 2.0 Hz, 1H), 5.89 (t, J=4.8 Hz, 1H), 4.78 (s, 1H),2.77 (t, J=8.0 Hz, 2H), 2.39-2.34 (m, 2H), 1.27-1.22 (m, 3H), 1.11 (d,J=7.2 Hz, 18H). LCMS: 395.1 [M+H]⁺.

Step 4:((5-(4-(2-Bromoethoxy)phenyl)-7,8-dihydronaphthalen-2-yl)oxy)triisopropylsilane101j

A mixture of 101i (68 g, 172 mmol), K₂CO₃ (71 g, 517 mmol) and1,2-dibromoethane (324 g, 1723 mmol) in CH₃CN (700 mL) was heated at 80°C. for 16 h. After cooling to room temperature, the reaction mixture wasconcentrated and purified by column chromatography on silica gel elutedwith 0-10% EtOAc in petroleum ether to afford 101j (20 g, 23%) as lightyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.26 (m, 2H), 6.94-6.82 (m,3H), 6.73 (d, J=2.0 Hz, 1H), 6.60 (dd, J=8.4, 2.0 Hz, 1H), 5.90 (t,J=4.8 Hz, 1H), 4.33 (t, J=6.4 Hz, 2H), 3.66 (t, J=6.4 Hz, 2H), 2.78 (t,J=8.0 Hz, 2H), 2.39-2.35 (m, 2H), 1.28-1.24 (m, 3H), 1.11 (d, J=7.2 Hz,18H).

Step 5:((6-Bromo-5-(4-(2-bromoethoxy)phenyl)-7,8-dihydronaphthalen-2-yl)oxy)triisopropylsilane 101k

To a mixture of 101i (37 g, 74 mmol) in DCM (400 mL) was added Py.HBr₃(23 g, 73 mmol) at 0° C. and the mixture was stirred for 20 minutes.Water (300 mL) was added to the reaction mixture and the mixture wasextracted with DCM (800 mL×2) and two layers were separated. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated to give 101k (40 g crude) as dark green oil which was usedin the next step directly. ¹H NMR (400 MHz, CDCl₃) δ 7.17 (d, J=8.4 Hz,2H), 6.97 (d, J=8.4 Hz, 2H), 6.67 (s, 1H), 6.55-6.48 (m, 2H), 4.35 (t,J=6.4 Hz, 2H), 3.68 (t, J=6.4 Hz, 2H), 2.98-2.93 (m, 4H), 1.28-1.20 (m,3H), 1.09 (d, J=7.2 Hz, 18H).

Step 6:((5-(4-(2-Bromoethoxy)phenyl)-6-phenyl-7,8-dihydronaphthalen-2-yl)oxy)triisopropylsilane101l

To a suspension of 101k (40 g, 69 mmol), phenylboronic acid (12 g, 103mmol) and Na₂CO₃(22 g, 207 mmol) in 1,4-dioxane (400 mL) and water (80mL) was added Pd(PPh₃)₄ (7.96 g, 6.89 mmol). The resulting mixture wasstirred at 80° C. under N₂ atmosphere for 2 hours. After cooling to roomtemperature, the reaction mixture was diluted with water (30 mL),extracted with DCM (30 ml×2) and two layers were separated. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated and theresidue was purified by column which was eluted with 0-10% EtOAc inhexanes to afford 101l (32g, 80%) as light yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 7.16-7.08 (m, 2H), 7.07-6.94 (m, 5H), 6.79-6.71 (m, 3H),6.66-6.60 (m, 1H), 6.59-6.52 (m, 1H), 4.26 (t, J=6.4 Hz, 2H), 3.66-3.59(m, 2H), 2.96-2.87 (m, 2H), 2.80-2.73 (m, 2H), 1.31-1.22 (m, 3H), 1.11(d, J=7.6 Hz, 18H).

Step 7:((cis-5-(4-(2-Bromoethoxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy)triisopropylsilane101m

A reaction mixture of 101l 32 g, 55 mmol) and 10% palladium hydroxide oncarbon (2.67 g, 1.9 mmol) in EtOH (500 mL) was stirred at 20° C. underH₂ atmosphere (30 psi) for 16 hours. The reaction mixture was filteredand concentrated to give 101m and the enantiomer (32 g crude) as lightyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.17-7.11 (m, 3H), 6.81-6.71 (m,4H), 6.64-6.54 (m, 1H), 6.51 (d, J=8.4 Hz, 2H), 6.29 (d, J=8.4 Hz, 2H),4.22 (d, J=4.8 Hz, 1H), 4.15 (t, J=6.4 Hz, 2H), 3.55 (t, J=6.4 Hz, 2H),3.41-3.32 (m, 1H), 3.06-2.97 (m, 2H), 2.17-2.06 (m, 1H), 1.79-1.77 (m,1H), 1.30-1.20 (m, 3H), 1.10 (d, J=6.8 Hz, 18H).

Step 8:3-(fluoromethyl)-1-(2-(4-((1R,2S)-2-phenyl-6-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy)ethyl)azetidine101n

A mixture of 101m and the enantiomer (30 g, 52 mmol), 3-(fluoromethyl)azetidine TFA salt (21 g, 103 mmol) and K₂CO₃ (28 g, 207 mmol) in CH₃CN(400 mL) was heated at 80° C. for 16 hours. After cooling to roomtemperature, the reaction mixture was filtered, concentrated and theresidue was purified by column eluted with 0-8% MeOH in DCM to afford101n and the enantiomer (20 g, 66%) as a light yellow oil. ¹H NMR (400MHz, CDCl₃) δ 7.21-7.12 (m, 3H), 6.86-6.73 (m, 4H), 6.64 (dd, J=8.4, 2.4Hz, 1H), 6.52 (d, J=8.8 Hz, 2H), 6.30 (d, J=8.8 Hz, 2H), 4.60-4.43 (m,2H), 4.24 (d, J=5.2 Hz, 1H), 3.85 (t, J=5.2 Hz, 2H), 3.48 (t, J=7.2 Hz,2H), 3.43-3.35 (m, 1H), 3.13 (t, J=6.8 Hz, 2H), 3.08-2.99 (m, 2H),2.93-2.73 (m, 3H), 2.22-2.07 (m, 1H), 1.88-1.76 (m, 1H), 1.35-1.22 (m,3H), 1.20-1.10 (m, 18H). LCMS: 588.4 [M+H]⁺.

Step 9: 101 and 102

To a solution of 101n and the enantiomer (30.0 g, 51.03 mmol) in THF(300 mL) was added 1 M TBAF (102 mL, 102 mmol) in THF. The mixture wasstirred at 20° C. for 16 hours. The mixture was concentrated andpurified by column eluted with 0-8% MeOH in DCM to give the crudeproduct (22 g). The crude product was purified by reverse phasechromatography (CH₃CN 50-90%/0.05% NH₄OH in water) to afford thecis-mixture 101 and 102 which was further separated by chiral SFC togive two pure enantiomers 101 and 102.

Example 102(1S,2R)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-phenyl-tetralin-6-ol102

Compound 102 was made by the procedures of Example 101.

Example 103(1S,2R)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(4-fluorophenyl)tetralin-6-ol103

Compound 103 was made by the procedures of Example 106.

Example 104(1R,2R)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-phenyl-tetralin-6-ol104

Compound 104 was made by the procedures of Example 105.

Example 105(1S,2S)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-phenyl-tetralin-6-ol105 Step 1:3,5-Difluoro-4-(6-((triisopropylsilyl)oxy)-3,4-dihydronaphthalen-1-yl)phenol105a

To a solution of(6-triisopropylsilyloxy-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate 101h 1.0 g, 2.22 mmol), Pd(PPh₃)₄(0.22 mmol),(2,6-difluoro-4-hydroxy-phenyl)boronic acid (463 mg, 2.66 mmol) in1,4-dioxane (10 mL) and water (3 mL) was added NaHCO₃ (705 mg, 6.65mmol) and 90° C. under N₂ atmosphere for 3 hours. The reaction mixturewas diluted with EtOAc (20 mL) and water (10 mL), separated and theaqueous layer was extracted with EtOAc (10 mL×2), dried over Na₂SO₄,concentrated and purified by column (0-10% EtOAc in hexanes) to afford105a (750 mg, 78%) as purple oil. LCMS: 431.2 [M+H]⁺.

Step 2:4-(2-Bromo-6-((triisopropylsilyl)oxy)-3,4-dihydronaphthalen-1-yl)-3,5-difluorophenol105b

To a solution of 105a (650 mg, 1.28 mmol) in DCM (10 mL) was addedpyridinium tribromide (494 mg, 1.55 mmol) at 0° C. The reaction mixturewas stirred for 2 hours. The reaction mixture was poured into ice-water(10 mL) slowly and was extracted with DCM (20 mL×2). The combinedorganic layers were dried over Na₂SO₄ and concentrated to give 105b (650mg, 84% yield) as a brown oil which was used for the next step directly.

Step 3:3,5-Difluoro-4-(2-phenyl-6-((triisopropylsilyl)oxy)-3,4-dihydronaphthalen-1-yl)phenol105c

To a solution of 105b (650 mg, 1.28 mmol) and phenylboronicacid (187 mg,1.53 mmol) in dioxane (10 mL) and water (3 mL) was added Na₂CO₃ (270 mg,2.55 mmol) and Pd(PPh₃)₄(74 mg, 0.06 mmol). The reaction mixture wasstirred under N₂ atmosphere at 90° C. for 2 hours. The reaction mixturewas cooled down to room temperature and diluted with EtOAc (20 mL) andwater (5 mL). The aqueous layer was extracted with EtOAc (5 mL×2). Thecombined organic layers were dried over Na₂SO₄, concentrated and theresidue was purified by column eluted with 0-10% EtOAc in hexanes toafford 105c (500 mg, 67%) as colorless oil. LCMS: 507.1 [M+H]⁺.

Step 4:cis-3,5-Difluoro-4-2-phenyl-6-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)phenol105d

To a solution of 105c (500 mg, 0.99 mmol) in EtOH (10 mL) was added 20%Pd(OH)₂/C (250 mg) and then stirred under a balloon of H₂ for 16 hours.The reaction mixture was filtered and concentrated to afford racemic105d (500 mg crude) as colorless oil which was used in the next stepdirectly. LCMS: 509.3 [M+H]⁺.

Step 5:cis-(5-(4-(2-Bromoethoxy)-2,6-difluorophenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy)triisopropylsilane105e

A mixture of racemic 105d (0.5 g, 0.98 mmol), 1,2-dibromoethane (1846mg, 9.83 mmol) and K₂CO₃ (679 mg, 4.91 mmol) in CH₃CN (5 mL) was heatedat 80° C. for 16 hours. The reaction mixture was diluted with EtOAc (20mL) and washed with water (5 mL), dried over Na₂SO₄ and concentrated.The residue was purified by column eluted with 0-10% EtOAc in hexanes togive racemic 105e (300 mg crude) as colorless oil which was carried overto the next step.

Step 6:cis-1-(2-(3,5-Difluoro-4-(2-phenyl-6-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy)ethyl)-3-(fluoromethyl)azetidine106f

A mixture of racemic 106e (300 mg, 0.49 mmol), 3-(fluoromethyl)azetidinetrifluoroacetic acid salt (198 mg, 0.97 mmol) and K₂CO₃ (202 mg, 1.46mmol) in CH₃CN (5 mL) was heated at 80° C. for 16 hours. The reactionmixture was concentrated and the residue was purified by column elutedwith 0-8.6% MeOH in DCM to afford racemic 106f (240 mg, 79% yield) as ayellow oil.

Step 7: 104 and 105

To a solution of racemic 106f (240 mg, 0.38 mmol) in THF (2 mL) wasadded 1 M TBAF (0.5 mL, 0.50 mmol) in THF. The mixture was stirred at20° C. for 16 hours. The reaction mixture was concentrated and dilutedwith EtOAc (10 mL), washed with brine (3 mL×6). The organic layer wasdried over Na₂SO₄, concentrated and the residue was purified by reversephase chromatography (CH₃CN 49-69%/0.05% NH₄OH in water) to afford thecis-mixture of 104 and 105 as a white solid (60 mg, 33% yield). ¹H NMR(400 MHz, CD₃OD) δ 7.18-7.00 (m, 3H), 6.99-6.87 (m, 2H), 6.68 (d, J=8.0Hz, 1H), 6.60 (s, 1H), 6.48 (dd, J=2.0, 8.0 Hz, 1H), 6.21 (s, 2H), 4.61(m, 1H), 4.55-4.38 (m, 2H), 3.87 (m, 2H), 3.48 (t, J=7.6 Hz, 2H),3.42-3.35 (m, 1H), 3.17 (t, J=7.2 Hz, 2H), 3.06-2.95 (m, 2H), 2.93-2.71(m, 3H), 2.49-2.29 (m, 1H), 1.84 (m, 1H). LCMS: 468.2 [M+H]⁺. LCMS:468.2 [M+H]⁺.

The two enantiomers were separated by chiral SFC. Chiral SFC condition:AD (250 mm×30 mm, 10 μm), supercritical CO₂/MeOH (0.1% NH₃.H₂O)=30%.105: Rt=4.816 min, 104: Rt=5.269 min.

Example 106(1R,2S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(4-fluorophenyl)tetralin-6-ol106 Step 1:((5-(4-(2-Bromoethoxy)phenyl)-6-(4-fluorophenyl)-7,8-dihydronaphthalen-2-yl)oxy)triisopropylsilane106a

To a suspension of[6-bromo-5-[4-(2-bromoethoxy)phenyl]-7,8-dihydronaphthalen-2-yl]oxy-triisopropyl-silane101k (500 mg, 0.86 mmol), 4-fluorophenylboronicacid (181 mg, 1.29 mmol)and Na₂CO₃ (273 mg, 2.58 mmol) in 1,4-dioxane (5 mL) and water (1 mL)was added Pd(PPh₃)₄(100 mg, 0.09 mmol) and stirred at 80° C. under N₂atmosphere for 2 hours. After cooling to room temperature, the reactionmixture was diluted with water (10 mL), extracted with DCM (20 ml×2) andtwo layers were separated. The combined organic layers were dried overNa₂SO₄, filtered, concentrated and purified by column eluted with 0-10%EtOAc in hexanes to afford 106a (450 mg, 88% yield) as light yellow oil.¹H NMR (400 MHz, CDCl₃) δ 6.98-6.89 (m, 4H), 6.82-6.69 (m, 5H),6.63-6.58 (m, 1H), 6.56-6.50 (m, 1H), 4.25 (t, J=6.4 Hz, 2H), 3.62 (t,J=6.4 Hz, 2H), 2.95-2.83 (m, 2H), 2.77-2.66 (m, 2H), 1.26-1.23 (m, 3H),1.09 (d, J=7.2 Hz, 18H).

Step 2:cis-((5-(4-(2-Bromoethoxy)phenyl)-6-(4-fluorophenyl)-5,6,7,8-tetrahydronaphthalen-2-yl)oxy)triisopropylsilane106b

A reaction mixture of 106a (from step 1, 450 mg, 0.76 mmol) and 10%palladium hydroxide on carbon (40 mg, 0.03 mmol) in ethanol (6 mL) wasstirred at 20° C. under H₂ atmosphere (balloon) for 16 hours. Thereaction mixture was filtered and the filtrate was concentrated to give106b and the enantiomer (450 mg crude) as light yellow oil. ¹H NMR (400MHz, CDCl₃) δ 6.88-6.80 (m, 1H), 6.77-6.68 (m, 2H), 6.61 (dd, J=8.0, 2.4Hz, 1H), 6.53 (d, J=8.8 Hz, 2H), 6.30 (d, J=8.8 Hz, 2H), 4.21-4.11 (m,3H), 3.56 (t, J=6.4 Hz, 2H), 3.36-3.32 (m, 1H), 3.06-2.90 (m, 2H),2.20-2.00 (m, 1H), 1.76-1.73 (m, 1H), 1.27-1.23 (m, 3H), 1.10 (d, J=6.8Hz, 18H).

Step 3:cis-3-(Fluoromethyl)-1-(2-(4-(2-(4-fluorophenyl)-6-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy)ethyl)azetidine 106c

A mixture of 106b and the enantiomer (400 mg, 0.67 mmol),3-(fluoromethyl)azetidine TFA salt (272 mg, 1.34 mmol) and K₂CO₃ (277mg, 2.01 mmol) in CH₃CN (5 mL) was heated at 80° C. for 16 hours. Aftercooling to room temperature, the reaction mixture was concentrated andpurified by column eluted with 0-8% MeOH in DCM to afford 106c and theenantiomer (350 mg, 86%) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃)δ 7.71 (d, J=8.0 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 6.77-6.69 (m, 2H),6.61 (dd, J=8.4, 2.4 Hz, 1H), 6.49 (d, J=8.8 Hz, 2H), 6.27 (d, J=8.8 Hz,2H), 4.60-4.39 (m, 2H), 4.21 (d, J=4.8 Hz, 1H), 3.83 (t, J=5.2 Hz, 2H),3.54-3.38 (m, 3H), 3.12 (t, J=6.8 Hz, 2H), 3.05-2.94 (m, 5H), 2.90-2.66(m, 3H), 2.26-2.16 (m, 1H), 1.79-1.76 (m, 1H), 1.28-1.20 (m, 3H), 1.10(d, J=6.4 Hz, 18H). LCMS: 606.3 [M+H]⁺.

Step 4: 106 and 103

To a solution of 106c (350 mg, 0.58 mmol) in THF (4 mL) was added 1 MTBAF (1 mL, 1 mmol) in THF. The mixture was stirred at 20° C. for 16hours. The mixture was diluted with EtOAc (15 mL), washed with brine (5mL×7) and two layers were separated. The combined organic layers weredried over Na₂SO₄, filtered and concentrated and further purified byreverse phase chromatography (CH₃CN 53-83%/0.05% NH₄OH in water) toafford the cis-mixture of 106 and 103 as white solid (150 mg, 58%yield). ¹H NMR (400 MHz, CD₃OD) δ 6.93-6.77 (m, 1H), 6.74-6.62 (m, 1H),6.60-6.46 (m, 1H), 6.36 (d, J=8.4 Hz, 1H), 4.58-4.39 (m, 1H), 4.20 (d,J=5.2 Hz, 1H), 3.90 (t, J=5.2 Hz, 2H), 3.52 (t, J=7.6 Hz, 2H), 3.20 (t,J=7.6 Hz, 2H), 3.10-2.97 (m, 2H), 2.92-2.75 (m, 3H), 2.30-2.09 (m, 1H),1.77-1.75 (m, 1H). LCMS: 450.2 [M+H]⁺. The enantiomeric compounds wereseparated with chiral SFC. Chiral SFC condition: OD (250 mm×30 mm, 10μm), supercritical CO₂/EtOH (0.1% NH₃.H₂O)=35%. 103 Rt=4.81 min, 106Rt=5.58 min.

Example 108(5S,6S)-6-(4,4-difluorocyclohexyl)-5-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol108

Compound 108 was made by the procedures of Example 110.

Example 110(5R,6R)-6-(4,4-difluorocyclohexyl)-5-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol110 Step 1:((5-(4-(2-Bromoethoxy)phenyl)-6-(4,4-difluorocyclohex-1-en-1-yl)-7,8-dihydronaphthalen-2-yl)oxy)triisopropylsilane 110a

To a suspension of((6-Bromo-5-(4-(2-bromoethoxy)phenyl)-7,8-dihydronaphthalen-2-yl)oxy)triisopropylsilane 101k (500 mg, 0.86 mmol),2-(4,4-difluorocyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(252 mg, 1.03 mmol) and Na₂CO₃ (273.9 mg, 2.58 mmol) in 1,4-dioxane (5mL) and water (1 mL) was added Pd(PPh₃)₄(99 mg, 0.09 mmol) and theresulting mixture was stirred at 80° C. under N₂ atmosphere for 2 hours.After cooling to room temperature, the reaction mixture was diluted withwater (10 mL), extracted with DCM (20 ml×2). The combined organic layerswere dried over Na₂SO₄, filtered, concentrated and the residue waspurified by column eluted with 0-10% EtOAc in hexanes to afford 110a(400 mg, 75% yield) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.07(d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 6.69 (s, 1H), 6.59-6.51 (m,2H), 5.20-5.17 (m, 1H), 4.36-4.27 (m, 2H), 3.67 (t, J=6.4 Hz, 2H), 2.81(t, J=8.0 Hz, 2H), 2.50-2.43 (m, 2H), 2.43-2.32 (m, 2H), 2.13-2.10 (m,2H), 1.88-1.85 (m, 2H), 1.26-1.20 (m, 3H), 1.10 (d, J=7.6 Hz, 18H).

Step 2:cis-((5-(4-(2-Bromoethoxy)phenyl)-6-(4,4-difluorocyclohexyl)-5,6,7,8-tetrahydronaphthalen-2-yl)oxy)triisopropylsilane110b

A mixture of 110a 400 mg, 0.65 mmol) and 10% palladium hydroxide oncarbon (50 mg, 0.04 mmol) in ethanol (6 mL) was stirred at 20° C. underH₂ atmosphere (balloon) for 16 hours. The reaction mixture was filteredand the filtrate was concentrated to give 110b and the enantiomer (400mg crude) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.89 (d, J=8.4Hz, 2H), 6.74 (d, J=8.8 Hz, 2H), 6.72-6.67 (m, 1H), 6.64 (s, 1H), 6.55(dd, J=8.4, 2.4 Hz, 1H), 4.23 (t, J=6.4 Hz, 2H), 4.14 (d, J=4.8 Hz, 1H),3.73-3.71 (m, 1H), 3.64-3.54 (m, 2H), 2.98-2.89 (m, 1H), 2.86-2.73 (m,1H), 2.10-2.08 (m, 2H), 1.83-1.69 (m, 2H), 1.65-1.51 (m, 5H), 1.47-1.34(m, 2H), 1.21-1.17 (m, 3H), 1.07 (d, J=7.2 Hz, 18H).

Step 3:cis-1-(2-(4-(2-(4,4-Difluorocyclohexyl)-6-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy)ethyl)-3-(fluoromethyl)azetidine110c

A mixture of 110b and the enantiomer (400 mg, 0.64 mmol),3-(fluoromethyl)azetidine TFA salt (261 mg, 1.29 mmol) and K₂CO₃ (267mg, 1.93 mmol) in CH₃CN (6 mL) was heated at 80° C. for 16 hours. Aftercooling to room temperature, the reaction mixture was concentrated andthe residue was purified by column eluted with 0-8% MeOH in DCM toafford 110c and the enantiomer (300 mg, 74% yield) as a light yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 6.88 (d, J=8.4 Hz, 2H), 6.76-6.69 (m,3H), 6.66 (s, 1H), 6.56 (d, J=8.4 Hz, 1H), 4.59-4.42 (m, 2H), 4.14 (m,1H), 3.90 (t, J=5.6 Hz, 2H), 3.48 (t, J=7.2 Hz, 2H), 3.14 (t, J=7.2 Hz,2H), 2.99-2.72 (m, 6H), 2.22-1.88 (m, 2H), 1.76-1.72 M, 2H), 1.43-1.40(m, 2H), 1.32-1.14 (m, 7H), 1.08 (d, J=7.2 Hz, 18H). LCMS: 630.4 [M+H]⁺.

Step 4: 108 and 110

To a solution of 110c and the enantiomer (250 mg, 0.40 mmol) in THF (4mL) was added 1 M TBAF (0.79 mL, 0.79 mmol) in THF. The mixture wasstirred at 20° C. for 16 hours. The mixture was diluted with EtOAc (15mL), washed with brine (5 mL×7). The organic layer was dried overNa₂SO₄, filtered and concentrated which was further purified reversephase chromatography (CH₃CN 54-84%/0.05% NH₄OH in water) to afford thecis-mixture of 108 and 110 as white solid (140 mg, 74% yield). ¹H NMR(400 MHz, CD₃OD) δ 6.94 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 6.65(d, J=8.4 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 6.45 (dd, J=8.4, 2.4 Hz, 1H),4.55-4.39 (m, 2H), 4.14 (d, J=4.4 Hz, 1H), 3.95 (t, J=5.2 Hz, 2H), 3.53(t, J=7.6 Hz, 2H), 3.22 (t, J=7.6 Hz, 2H), 2.96-2.77 (m, 5H), 2.17-1.97(m, 2H), 1.80-1.62 (m, 4H), 1.47-1.32 (m, 3H), 1.29-1.13 (m, 2H),1.12-1.01 (m, 1H). LCMS: 474.2 [M+H]⁺. The cis-mixture was furtherseparated by chiral SFC to give two pure enantiomers. Chiral SFCcondition: AD (250 mm×30 mm, 10 μm), supercritical CO₂/EtOH (0.1%NH₃.H₂O)=40%. First eluting enantiomer: Rt=5.214 min, Second elutingenantiomer: Rt=5.786 min.

Example 116(5S,6R)-5-(4-(2-(3-(difluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol116

Compound 116 was made by the procedures of Example 118.

Example 118(5R,6S)-5-(4-(2-(3-(difluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol118 Step 1:cis-3-(Difluoromethyl)-1-(2-(4-(2-phenyl-6-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy)ethyl)azetidine 118a

A mixture of((5-(4-(2-Bromoethoxy)phenyl)-6-phenyl-7,8-dihydronaphthalen-2-yl)oxy)triisopropylsilane101l 500 mg, 0.86 mmol), 3-(difluoromethyl) azetidine hydrochloride (248mg, 1.73 mmol) and K₂CO₃ (477 mg, 3.45 mmol) in CH₃CN (6 mL) was heatedat 80° C. for 16 hours. After cooling to room temperature, the reactionmixture was filtered and concentrated. The residue was purified bycolumn eluted with 0-8% MeOH in DCM to afford 118a and the enantiomer(400 mg, 76% yield) as light yellow oil. LCMS: 606.3 [M+H]⁺.

Step 2: 116 and 118

To a solution of 118a (400 mg, 0.66 mmol) in THF (4 mL) was added 1 MTBAF (1.3 mL, 1.3 mmol) in THF. The mixture was stirred at 20° C. for 16hours. The mixture was diluted with EtOAc (15 mL), washed with brine (5mL×7). Organic layer was dried over Na₂SO₄, filtered and concentratedwhich was further purified reverse phase chromatography (CH₃CN54-84%/0.05% NH₄OH in water) to afford the cis-mixture of 116 and 118 asa white solid (150 mg, 50% yield). ¹H NMR (400 MHz, CD₃OD) δ 7.19-7.06(m, 3H), 6.86-6.77 (m, 2H), 6.74-6.63 (m, 2H), 6.58-6.46 (m, 3H), 6.33(d, J=8.4 Hz, 2H), 6.22-5.84 (m, 1H), 4.22 (d, J=5.2 Hz, 1H), 3.89 (t,J=5.2 Hz, 2H), 3.60-3.45 (m, 2H), 3.33-3.28 (m, 2H), 3.12-2.88 (m, 3H),2.83 (t, J=5.2 Hz, 2H), 2.39-2.06 (m, 1H), 1.88-1.70 (m, 1H). LCMS:450.2 [M+H]⁺.

The cis-mixture was further separated by chiral SFC to give two pureenantiomers. Chiral SFC condition: AY (250 mm×30 mm, 10 μm),supercritical CO₂/EtOH (0.1% NH₃.H₂O)=30%. 118: Rt=3.776 min, 116:Rt=4.320 min.

Example 121(S)-1′-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3′,4′-dihydro-1′H-spiro[cyclopentane-1,2′-naphthalen]-6′-ol121

Step 1:6′-methoxy-3′,4′-dihydro-1′H-spiro[cyclopentane-1,2′-naphthalen]-1′-one121a

To a 500-mL round bottom flask (RBF) equipped with a reflux condenserwas added 6-methoxytetralin-1-one 101a (5 g, 28.375 mmol), followed bybenzene (0.175 M, 162 mL), potassium tert-butoxide (7.3g, 2.3 equiv.,65.263 mmol) and 1,4-dibromobutane (6.4g, 1.05 equiv., 29.794 mmol). Themixture was then heated to reflux for 3 h and then stirred overnight atroom temperature. The reaction was incomplete and to the solution wasadded additional potassium tert-butoxide (7.3g, 2.3 equiv., 65.263 mmol)and 1,4-dibromobenzene (6.4g, 1.1 equiv., 9.553 mmol). After 3 h atreflex, the reaction was quenched with the addition of sat. aq NH₄Clsolution, extracted with iPrOAc, dried with MgSO₄, filtered andconcentrated. Purification by silica gel column chromatography withiPrOAc/heptanes furnished 121a (2 g, 30.6% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 7.83 (d, J=8.7 Hz, 1H), 6.91-6.79 (m, 2H), 3.82 (s, 3H), 2.93(t, J=6.2 Hz, 2H), 2.01-1.87 (m, 5H), 1.73-1.59 (m, 4H), 1.58-1.45 (m,2H).

Step 2:1′-(4-bromophenyl)-6′-methoxy-3′,4′-dihydro-1′H-spiro[cyclopentane-1,2′-naphthalen]-1′-ol121b

To a 250-mL round-bottom flask was added 1,4-dibromobenzene (2.3g, 1.1equiv., 9.553 mmol), tetrahydrofuran (0.3 M, 29 mL). The mixture wascooled to −78° C. and n-butyl lithium (2.5 M) in hexanes (4.2 mL, 1.2equiv., 10.42 mmol) was added drop-wise. The reaction was then allowedto stir at −78° C. for 30 min. Then 121a (2 g, 8.684 mmol) was added andthe reaction was stirred at −78° C. for 1 h. Once starting material wasconsumed as monitored by TLC, the reaction was quenched with theaddition of sat. aq NH₄Cl solution, extracted with iPrOAc, dried withMgSO₄, filtered and concentrated. Purification by silica gel columnchromatography (0-100% iPrOAc/Heptanes) gave 121b (2.7 g, 80% yield). ¹HNMR (400 MHz, DMSO-d₆) δ 7.43-7.32 (m, 2H), 7.22-7.03 (m, 3H), 6.67 (d,J=8.0 Hz, 2H), 3.73 (s, 3H), 2.86 (qdd, J=14.1, 8.1, 4.8 Hz, 2H),1.91-1.25 (m, 9H), 0.68 (ddd, J=11.4, 6.4, 4.3 Hz, 1H).

Step 3:1′-(4-bromophenyl)-6′-methoxy-3′,4′-dihydro-1′H-spiro[cyclopentane-1,2′-naphthalene121c

To a 250-mL round-bottom flask was added 121b (0.775 g, 2.00 mmol),dichloromethane (0.5 M, 4 mL) and triethylsilane (0.64 g, 2 equiv., 4.00mmol). The reaction was then cooled to 0° C. and trifluoroacetic acid(0.17 mL, 1.1 equiv., 2.20 mmol) was added drop-wise. After 5 min 0° C.,the reaction was complete and the reaction was quenched with theaddition of sat. aq NaHCO₃ solution, extracted with iPrOAc, dried withMgSO₄, filtered and concentrated. Purification by silica gel columnchromatography (0-20% iPrOAc/Heptanes) furnished 121c (0.615 g, 82.8%yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.45-7.36 (m, 2H), 6.96-6.89 (m,2H), 6.74-6.68 (m, 2H), 6.60 (dd, J=8.5, 2.7 Hz, 1H), 3.74 (s, 1H), 3.70(s, 3H), 2.99-2.78 (m, 2H), 1.83-1.34 (m, 9H), 0.82-0.75 (m, 1H).

Step 4:1′-(4-bromophenyl)-3′,4′-dihydro-1′H-spiro[cyclopentane-1,2′-naphthalen]-6′-ol121d

To a 250-mL round-bottom flask was added 121c (0.615 g, 1.66 mmol) anddichloromethane (0.25 M, 6.6 mL). The reaction was cooled to −78° C. andboron tribromide (1 M) in dichloromethane (2.1 mL, 1.25 equiv., 2.07mmol) was added drop-wise. Once the addition was complete the reactionwas allowed to warm to room temperature for 4 h. It was quenched withthe addition of sat. aq NaHCO₃ solution, extracted with iPrOAc, driedwith MgSO₄, filtered and concentrated. Purification by silica gel columnchromatography (0-100% iPrOAc/Heptanes) furnished 121d (520 mg, 87.9%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (s, 1H), 7.44-7.34 (m, 2H),6.97-6.87 (m, 2H), 6.62-6.52 (m, 2H), 6.43 (dd, J=8.3, 2.6 Hz, 1H), 3.68(s, 1H), 2.88-2.70 (m, 2H), 1.79-1.46 (m, 6H), 1.36 (dddd, J=23.5, 14.3,12.3, 7.4 Hz, 3H), 0.79 (ddd, J=12.4, 7.9, 4.9 Hz, 1H).

Step 5: 121 and 122

To a 20-mL sealed tube was added 121d (520 mg, 1.455 mmol), cuprousiodide (139 mg, 0.5 equiv., 0.7277 mmol), potassium carbonate (1.2g, 6equiv., 8.732 mmol), butyronitrile (0.15 M, 9.7 mL) and2-[3-(fluoromethyl)azetidin-1-yl]ethanol 121e (970 mg, 5 equiv., 7.277mmol). The reaction was purged with nitrogen and heated to 170° C. for72 h. The reaction mixture was cooled to room temperature, filtered,concentrated and purified by chiral reverse phase HPLC to furnish aracemic mixture of 121 and 122 (6 mg, 1% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 9.00 (s, 1H), 6.89-6.82 (m, 2H), 6.78-6.71 (m, 2H), 6.58 (d,J=8.4 Hz, 1H), 6.52 (d, J=2.5 Hz, 1H), 6.41 (dd, J=8.3, 2.5 Hz, 1H),4.55 (d, J=6.2 Hz, 1H), 4.43 (d, J=6.3 Hz, 1H), 3.84 (t, J=5.6 Hz, 2H),3.60 (s, 1H), 3.30 (d, J=1.8 Hz, 2H), 2.98 (dd, J=7.2, 5.8 Hz, 2H),2.83-2.63 (m, 5H), 1.81-1.71 (m, 1H), 1.70-1.24 (m, 8H), 0.79 (dt,J=12.9, 6.3 Hz, 1H). LCMS: 410.2 [M+H]⁺.

The two enantiomers were separated by chiral SFC. Chiral SFC condition:AA (4.6 mm×50 mm, 3 μm), supercritical CO₂/MeOH (0.1% NH₃.H₂O)=20%, flowrate 4 mL/min. 122: Rt=1.44 min, 121: Rt=1.0 min.

Example 122(R)-1′-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3′,4′-dihydro-1′H-spiro[cyclopentane-1,2′-naphthalen]-6′-ol122

Compound 122 was made by the procedures of Example 121.

Example 129(5S,6R)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol129

Step 1: 6-(Benzyloxy)-3,4-dihydronaphthalen-1(2H)-one 129a

To a mixture of 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one 101f (20.0 g,123.31 mmol) and benzyl bromide (20 mL, 246.62 mmol) in MeCN (70 mL) wasadded K₂CO₃ (33.2 g, 240.21 mmol) at 15° C. and the resulting mixturewas stirred for 3 hours. The mixture was filtered, concentrated and theresidue was purified by flash column chromatography eluted with 0-10%EtOAc in petroleum ether to afford 129a (26 g, 84% yield) as brown oil.¹H NMR (400 MHz, CDCl₃) δ 8.06-7.98 (m, 1H), 7.46-7.32 (m, 5H), 6.90 (d,J=8.8 Hz, 1H), 6.80 (s, 1H), 5.16-5.08 (m, 2H), 2.93 (t, J=6.0 Hz, 2H),2.62 (t, J=6.4 Hz, 2H), 2.17-2.06 (m, 2H).

Step 2: 6-(Benzyloxy)-3,4-dihydronaphthalen-1-yltrifluoromethanesulfonate 129b

To a solution of 129a (26.0 g, 103.05 mmol) in THF (300 mL) was addedLiHMDS (1M THF solution, 165 mL, 165 mmol) at −78° C. under N₂atmosphere. The mixture was stirred for 30 minutes and PhNTf₂ (55 g,154.57 mmol) was added to the mixture. The reaction mixture was slowlywarmed up to room temperature, and stirring was continued for 2 hours.Water (50 mL) was added to the reaction mixture and the mixture wasextracted with DCM (500 mL×2) and two layers were separated. Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column chromatographyeluted with 0-10% EtOAc in petroleum ether to afford 129b (36 g, 91%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.33 (m, 5H),7.26-7.24 (m, 1H), 6.84-6.80 (m, 2H), 5.85 (t, J=4.8 Hz, 1H), 5.06 (s,2H), 2.82 (t, J=8.0 Hz, 2H), 2.49-2.44 (m, 2H).

Step 3: 4-(6-(Benzyloxy)-3,4-dihydronaphthalen-1-yl)phenol 129c

To a mixture of 4-hydroxyphenylboronic acid (2.69 g, 19.51 mmol) indioxane (20 mL) and water (4 mL) was added 129b (5.0 g, 13.01 mmol),Pd(PPh₃)₄(1.5 g, 1.3 mmol), and Na₂CO₃ (4.14 g, 39.02 mmol). Theresulting mixture was stirred at 80° C. for 2 hours. The mixture wasfiltered through a Celite pad, concentrated in vacuo. The residue waspurified by silica gel chromatography eluted with 0-20% EtOAc inpetroleum ether to afford 129c (3.8 g, 89% yield) as brown oil. ¹H NMR(400 MHz, CDCl₃) δ 7.47-7.43 (m, 2H), 7.40-7.38 (m, 2H), 7.37-7.33 (m,1H), 7.25-7.20 (m, 2H), 6.96 (d, J=8.4 Hz, 1H), 6.89-6.81 (m, 3H),6.72-6.70 (m, 1H), 5.92 (t, J=4.8 Hz, 1H), 5.08 (s, 2H), 4.91 (s, 1H),2.82 (t, J=8.0 Hz, 1H), 2.40-2.35 (m, 2H).

Step 4: 4-(6-(Benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)phenol 129d

To a mixture of 129c (5.0 g, 15.23 mmol) in DCM (50 mL) was addedpyridinium tribromide (4.87 g, 15.23 mmol) at 0° C. and the reactionmixture was stirred for 1 hour. Water (100 mL) was added to the reactionmixture. The mixture was extracted with DCM (200 mL) and two layers wereseparated. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated which was purified by column chromatography on silica geleluted with 0-10% EtOAc in petroleum ether to give 129d (3.3 g, 53%yield) as brown oil. ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.29 (m, 5H), 7.11(d, J=8.8 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.80 (d, J=1.6 Hz, 1H),6.63-6.59 (m, 2H), 5.04 (s, 1H), 4.98 (s, 2H), 3.02-2.93 (m, 4H).

Step 5: 4-(6-(Benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol 129e

To a mixture of phenylboronic acid (480 mg, 3.51 mmol) in dioxane (10mL) and water (2 mL) was added 129d (0.9 g, 2.34 mmol), Pd(PPh₃)₄(270mg, 0.23 mmol) and Na₂CO₃ (0.74 g, 7.02 mmol), the resulting mixture wasstirred at 80° C. for 2 hours. The mixture was filtered through aCelite® (Johns Manville Co.) pad and concentrated in vacuo. The residuewas purified by silica gel chromatography eluted with 0-20% EtOAc inpetroleum ether to afford 129e (0.75 g, 98% yield) as brown oil. ¹H NMR(400 MHz, CDCl₃) δ 7.45-7.39 (m, 5H), 7.12-7.10 (m, 2H), 7.03-7.01 (m,3H), 7.14-7.09 (m, 2H), 7.08-7.00 (m, 3H), 6.92 (d, J=8.8 Hz, 2H), 6.87(d, J=2.4 Hz, 1H), 6.76-6.72 (m, 1H), 6.71-6.65 (m, 3H), 5.07 (s, 2H),4.93 (s, 1H), 2.97-2.91 (m, 2H), 2.81-2.75 (m, 2H).

Step 6:tert-Butyl-3-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy)azetidine-1-carboxylate 129f

To a solution of 129e (0.65 g, 1.61 mmol) in MeCN (60 mL) was addedCs₂CO₃ (1.57 g, 4.82 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate(0.59 g, 2.09 mmol) and the resulting mixture was heated at 80° C. for15 hours. After cooling to room temperature, the solid was removed byfiltration, washed with EtOAc (60 mL) and the filtrate was concentrated.The residue was dissolved in EtOAc (20 mL), washed with water (10 mL×2)and brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyeluted with 0-25% EtOAc in petroleum ether to give 129f (0.77 g, 86%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.30 (m, 5H),7.15-7.02 (m, 3H), 6.98-6.85 (m, 4H), 6.87 (s, 1H), 6.74-6.64 (m, 2H),6.59 (d, J=8.4 Hz, 2H), 5.08 (s, 2H), 4.88-4.81 (m, 1H), 4.27-4.25 (m,2H), 4.01-3.98 (m, 2H), 2.98-2.90 (m, 2H), 2.83-2.75 (m, 2H), 1.46 (s,9H).

Step 7: cis-tert-Butyl3-(4-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy)azetidine-1-carboxylate129g

To a mixture of tert-butyl3-[4-(6-benzyloxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]azetidine-1-carboxylate(From step 6, 0.9 g, 1.61 mmol) in EtOH (30 mL) was added 10% Pd(OH)₂/C(1.0 g, 0.71 mmol) under a balloon of hydrogen gas H₂ at 20° C. and theresulting mixture was stirred for 30 hours. The mixture was filteredthrough a Celite pad, concentrated in vacuo to afford racemic 129g (750mg) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.12 (m, 3H),6.84-6.75 (m, 3H), 6.72 (s, 1H), 6.64-6.57 (m, 1H), 6.39-6.29 (m, 4H),4.75-4.73 (m, 1H), 4.27-4.16 (m, 3H), 3.93-3.90 (m, 2H), 3.37-3.35 (m,1H), 3.11-2.96 (m, 2H), 2.21-2.10 (m, 1H), 1.81-1.78 (m, 1H), 1.44 (s,9H).

Step 8:cis-5-(4-(Azetidin-3-yloxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol129h

To a solution of racemic 129g (750 mg, 1.59 mmol) in dioxane (10 mL) wasadded concentrated H₂SO₄ (700 μL, 12.88 mmol) at 0° C. and the reactionmixture was stirred for 30 minutes. The solution was poured intosaturated aqueous NaHCO₃ (10 mL), extracted with EtOAc (40 mL×2). Thecombined organic layers were dried over Na₂SO₄ and concentrated to giveracemic 127h (550 mg) as yellow oil. The product was carried over to thenext step without further purification.

Step 9: 129 and 130

To a solution of racemic 129h (550 mg, 1.48 mmol) in DMF (5 mL) wasadded 1-iodo-3-fluoropropane (278 mg, 1.48 mmol) and DIPEA (0.79 mL,4.44 mmol) at 25° C. and the reaction mixture was stirred for 16 hours.The reaction mixture was purified by reverse phase chromatography(acetonitrile 60-90%/0.05% ammonia hydroxide in water) to afford thecis-mixture of racemic 129 and 130 (350 mg, 55% yield). ¹H NMR (400 MHz,CD₃OD) δ 7.13-7.10 (m, 3H), 6.80-6.78 (m, 2H), 6.69-6.64 (m, 2H),6.51-6.48 (m, 1H), 6.40 (d, J=8.4 Hz, 2H), 6.31 (d, J=8.4 Hz, 2H),4.87-4.82 (m, 1H), 4.68-4.65 (m, 1H), 4.51-4.36 (m, 2H), 4.19 (d, J=5.2Hz, 1H), 3.75-3.71 (m, 2H), 3.14-3.09 (m, 2H), 3.02-3.00 (m, 2H), 2.63(t, J=7.6 Hz, 2H), 2.21-2.18 (m, 1H), 1.78-1.70 (m, 3H). LCMS: 432.2[M+H]⁺.

The mixture was further separated to give the two enantiomers by chiralSFC. Chiral SFC condition: OD (250 mm×30 mm, 10 μm), supercriticalCO₂/MeOH (0.1% NH₃H₂O)=40%. 130: Rt=3.921 min, 129: Rt=4.252 min.

Example 130(5R,6S)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol130

Compound 130 was made by the procedures of Example 129.

Example 131(5S,6R)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol131

Step 1:Triisopropyl((5-(4-nitrophenyl)-7,8-dihydronaphthalen-2-yl)oxy)silane131a

To a mixture of(6-triisopropylsilyloxy-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate 101h (10.0 g, 22.19 mmol), tetrakis triphenylphosphinepalladium, Pd(PPh₃)₄(2.56 g, 2.22 mol) and Na₂CO₃ (7.06 g, 66.58 mmol)and 4-nitrophenylboronic acid (5.56 g, 33.29 mmol) in dioxane (100 mL)and water (20 mL) was stirred at 80° C. under N₂ atmosphere for 12hours. The reaction mixture was diluted with water (500 mL), extractedwith DCM (800 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and purified by chromatography on silica eluted with petroleumether to afford 131a (7.8 g, 83%) as yellow oil. ¹H NMR (400 MHz, CDCl₃)δ 8.24 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 6.78-6.75 (m, 2H),6.64 (dd, J=2.4, 8.4 Hz, 1H), 6.07 (t, J=4.4 Hz, 1H), 2.81 (t, J=8.0 Hz,2H), 2.45-2.40 (m, 2H), 1.29-1.24 (m, 3H), 1.12 (d, J=8.0 Hz, 18H).

Step 2:((6-Bromo-5-(4-nitrophenyl)-7,8-dihydronaphthalen-2-yl)oxy)triisopropylsilane131b

To a mixture of 131a (19.0 g, 44.85 mmol) in DCM (200 mL) was addedpyridinium tribromide (14.34 g, 44.85 mmol) dropwise at 0° C. Thereaction mixture was stirred at 0° C. for 10 minutes. Water (300 mL) wasadded to the reaction mixture and the mixture was extracted with DCM(500 mL×2). Combined organic layers were dried over Na₂SO₄, filtered andconcentrated to give a dark green oil which was purified by columneluted with petroleum ether to give 131b (19 g, 84%) as light yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (d, J=8.8 Hz, 2H), 7.43 (d, J=8.8Hz, 2H), 6.71 (d, J=2.8 Hz, 1H), 6.54-6.51 (m, 1H), 6.35 (d, J=8.4 Hz,1H), 2.98 (m, 4H), 1.27-1.20 (m, 3H), 1.09 (d, J=6.8 Hz, 18H).

Step 3:Triisopropyl((5-(4-nitrophenyl)-6-phenyl-7,8-dihydronaphthalen-2-yl)oxy)silane131c

To a suspension of 131b (19.0 g, 37.81 mmol), phenylboronic acid (6.92g, 56.71 mmol) and Na₂CO₃ (12.02 g, 113.43 mmol) in dioxane (200 mL) andwater (40 mL) was added Pd(PPh₃)₄(4.37g, 3.78 mmol). The resultingmixture was stirred at 80° C. under N₂ atmosphere for 2 hours. Thereaction mixture was diluted with water (100 mL), extracted with EtOAc(200 mL×2). The combined organic layers were dried over Na₂SO₄, filteredand concentrated. The crude product was purified by column eluted withpetroleum ether to afford 131c (18.8 g, 99%) as light yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 8.08 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H),7.13-7.11 (m, 3H), 6.97-6.96 (m, 2H), 6.77 (s, 1H), 6.55-6.60 (m, 1H),6.47-6.51 (m, 1H), 2.92-2.98 (m, 2H), 2.78-2.85 (m, 2H), 1.23-1.31 (m,3H), 1.12 (d, J=7.2 Hz, 18H).

Step 4:4-(cis-2-Phenyl-6-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)aniline131d

To the mixture of 131c (9.4 g, 18.81 mmol) in ethanol (100 mL) was addedPd(OH)₂/C (2.64 g, 1.88 mmol) at 20° C. and stirred for 30 hours underone atmosphere of hydrogen gas H₂. The mixture was filtered through apad of Celite, and concentrated in vacuo to afford racemic 131d as brownoil which was used in the next step directly without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 7.19-7.14 (m, 3H), 6.86-6.74 (m,4H), 6.63 (d, J=2.0 Hz, 1H), 6.33 (d, J=8.4 Hz, 2H), 6.19 (d, J=8.4 Hz,2H), 4.19 (d, J=4.8 Hz, 1H), 3.37-3.33 (m, 1H), 3.05-2.94 (m, 2H),2.24-2.11 (m, 1H), 1.83-1.77 (m, 1H), 1.28-1.23 (m, 3H), 1.12 (d, J=7.2Hz, 18H). LCMS: m/z 472.1 [M+H+].

Step 5: cis-tert-Butyl3-((4-(2-phenyl-6-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)amino)azetidine-1-carboxylate 131e

To a solution of racemic 131d (5.0 g, 10.6 mmol) in EtOH (50 mL) wasadded 1-Boc-3-azetidinone (3.63 g, 21.2 mmol), HOAc (3.03 mL, 52.99mmol) in 25° C. and the reaction mixture was stirred for 30 minutesbefore the addition of NaBH₃CN (3.33 g, 52.99 mmol). The reactionmixture was stirred for another 4 hours. Water (100 mL) was added to themixture. The mixture was extracted with EtOAc (200 mL×2). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography on silicaeluted with 0-80% EtOAc in petroleum ether to afford racemic 131e (6 g,90%). ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.14 (m, 3H), 6.84-6.74 (m, 4H),6.63 (m, 1H), 6.22 (d, J=8.4 Hz, 2H), 6.16 (d, J=8.0 Hz, 2H), 4.24-4.05(m, 4H), 3.70-3.63 (m, 2H), 3.35-3.34 (m, 1H), 3.09-2.94 (m, 2H),2.22-2.05 (m, 1H), 1.82-1.78 (m, 1H), 1.44 (s, 9H), 1.27 (m, 3H), 1.13(d, J=6.4 Hz, 18H); LCMS: 649.4 [M+Na⁺].

Step 6:cis-N-(4-(2-Phenyl-6-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)azetidin-3-amine 131f

To a mixture of racemic 131e (6.0 g, 9.57 mmol) in dioxane (50 mL) wasadded concentrated H₂SO₄ (2.55 mL, 47.85 mmol). The reaction was stirredat 25° C. for 1 hour. The reaction was quenched with saturated NaHCO₃(30 mL), washed with EtOAc (50 mL×2). The combined organic layers weredried over anhydrous Na₂SO₄, and concentrated in vacuo to give racemic131f as yellow oil (5.0 g crude) which was used in the next stepdirectly without further purification. LCMS: m/z 527.3 [M+H]⁺.

Step 7:cis-1-(3-Fluoropropyl)-N-(4-(2-phenyl-6-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)azetidin-3-amine 131g

To a solution of racemic 131f (5.0 g, 9.49 mmol) in DMF (50 mL) wasadded 1-iodo-3-fluoropropane (1.78 g, 9.49 mmol) and DIPEA (5.07 mL,28.47 mmol) at 25° C. and stirred for 16 hours. The reaction mixture wasdiluted with EtOAc (500 mL), washed with water (200 mL×3). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified on silica gel column chromatographyeluted with 9-66% EtOAc in petroleum ether to afford racemic 131g (3.57g, 64%) as a light brown oil. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.11 (m,3H), 6.84-6.73 (m, 4H), 6.62 (m, 1H), 6.25-6.15 (m, 4H), 4.63-4.47 (m,2H), 4.42-4.27 (m, 3H), 4.19 (d, J=4.4 Hz, 1H), 3.82 (m, 2H), 3.39-3.25(m, 3H), 3.08-2.95 (m, 2H), 2.19-2.02 (m, 4H), 1.80 (m, 1H), 1.33-1.21(m, 3H), 1.12 (d, J=7.2 Hz, 18H). LCMS: 587.3 [M+H]⁺.

Step 8: 131 and 132

To a solution of TBAF (1 M in THF, 12 mL, 12 mmol) in THF (30 mL) wasadded racemic 131g (3.57 g, 6.08 mmol) at 20° C. and stirred for 16hours. The reaction mixture was diluted with EtOAc (500 mL), washed withwater (50 mL×3). The organic layer was dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified by silicagel column (eluted with 0-5% MeOH in DCM) to afford the cis-mixture(2.35 g, 90%) of racemic 131 and 132 as a light yellow oil. ¹H NMR (400MHz, CDCl₃) δ 7.13-7.06 (m, 3H), 6.81 (d, J=8.0 Hz, 2H), 6.68-6.63 (m,2H), 6.51-6.49 (m, 1H), 6.20 (m, 4H), 4.57-4.41 (m, 2H), 4.16-4.06 (m,4H), 3.46-3.39 (m, 2H), 3.30-3.24 (m, 1H), 3.06-2.90 (m, 4H), 2.26-2.12(m, 1H), 1.94-1.69 (m, 3H). LCMS: 431.2 [M+H]⁺.

The cis-mixture was further separated to two pure enantiomers by chiralSFC. Chiral SFC condition: OD, 250 mm×30 mm, 10 m; supercriticalCO₂/EtOH (0.1% NH₃.H₂O)=35%, 132: Rt=4.855 min, 131: Rt=5.374 min.

Example 132(5R,6S)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol132

Compound 132 was made by the procedures of Example 131.

Example 901: Breast Cancer Cell ERa High Content Fluorescence ImagingDegradation Assay

MCF7 breast cancer cells were seeded on day 1 at a density of 10,000cells per well in 384 well poly-lysine coated tissue culture plate(Greiner # T-3101-4), in 50 L/well RPMI (phenol red free), 10% FBS(Charcoal stripped), containing L-glutamine. On day 2, compounds wereprepared at 2 compound source concentrations: 100 M and 1 M (ultimatelyto give 2 overlapping titration curves), in a Labcyte low dead volumeplate, 10 μL/well, and 10 μL of DMSO in designated wells for backfill,and 5 M Fulvestrant (control compound) in designated wells. Compoundsand controls were dispensed using a Labcyte Echo acoustic dispenser todispense compounds with a pre-defined serial dilution (1.8×, 10 point,in duplicate) and appropriate backfill and control compounds (finaltotal volume transferred was 417.5 nL and compound dispense volumeranges from 2.5 nL to 417.5 nL; 0.84% DMSO (v/v) final), ultimatelyproducing a concentration range from 0.05 nM to 835 nM. Cell plates wereincubated at 37° C., for 4 hours. Fixation and permeabilization werecarried out using a Biotek EL406 plate washer and dispenser as follows.Cells were fixed by addition of 15 μL of 16% paraformaldehyde (ElectronMicroscopy Sciences #15710-S) directly to the 50 μL cell culture mediumin each well using the peristaltic pump 5 μL cassette on a Biotek EL406(final concentration of formaldehyde was 3.7% w/v). Samples wereincubated 30 minutes. Well contents was aspirated and 50 μL/well ofPhosphate Buffered Saline (PBS) containing 0.5% w/v bovine serumalbumen, 0.5% v/v Triton X-100 (Antibody Dilution Buffer) was added toeach well. Samples were incubated for 30 minutes. Well contents wereaspirated and washed 3 times with 100 μL/well of PBS. Immunofluorescencestaining of estrogen receptor alpha (ESR1) was carried out using aBiotek EL406 plate washer and dispenser as follows. The well supernatantwas aspirated from the wells and 25 μL/well of anti-ESR1 mAb (F10)(Santa Cruz sc-8002) diluted 1:1000 in Antibody Dilution Buffer wasdispensed. Samples were incubated for 2 hours at room temperature.Samples were washed 4 times with 100 μL/well of PBS. 25 μL(microliters)/well of secondary antibody solution (Alexafluor® 488conjugate anti-mouse IgG (LifeTechnologies #A21202) diluted 1:1000 andHoechst 33342 1 μg/ml diluted in Antibody Dilution Buffer) weredispensed into each well. Samples were incubated for 2 hours at roomtemperature. Samples were washed 3 times with 100 μL/well of PBS using aBiotek EL406. Quantitative fluorescence imaging of ESR1 was carried outusing a Cellomics Arrayscan V® (Thermo). Fluorescence images of thesamples (Channel 1: XF53 Hoechst (DNA stain); Channel 2: XF53 FITC (ESR1stain)) were acquired using a Cellomics VTI Arrayscan using theBioapplication “Compartmental Analysis” using the auto-exposure (basedon DMSO control wells) setting “peak target percentile” set to 25%target saturation for both channels. Channel 1 (DNA stain) was used todefine the nuclear region (Circ). Measurements of “Mean_CircAvgIntCh2”,which is the Alexafluor 488 fluorescence intensity (ESR1) within thenuclear region, was measured on a per cell basis and averaged over allthe measured cells. Data analysis was carried out using GenedataScreener Software, with DMSO and 5 nM Fulvestrant treated samples beingused to define the 0% and 100% changes in ESR1. The “Robust Fit” methodwas used to define the inflexion point of curve (EC₅₀) and the plateauof the maximal effect (Sinf). Degradation data for exemplary Formula Icompounds is reported as ER-alpha MCF7 HCS S_(inf)(%) values in Table 1.

Example 902 In Vitro Cell Proliferation Assay

Efficacy of estrogen receptor modulator compounds and chemotherapeuticcompounds are measured by a cell proliferation assay employing thefollowing protocol (Mendoza et al (2002) Cancer Res. 62:5485-5488).

The CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneousmethod to determine the number of viable cells in culture based onquantitation of the ATP present, which signals the presence ofmetabolically active cells. The CellTiter-Glo® Assay is designed for usewith multiwell plate formats, making it ideal for automatedhigh-throughput screening (HTS), cell proliferation and cytotoxicityassays. The homogeneous assay procedure involves adding a single reagent(CellTiter-Glo® Reagent) directly to cells cultured inserum-supplemented medium. Cell washing, removal of medium or multiplepipetting steps are not required. The Cell Titer-Glo® Luminescent CellViability Assay, including reagents and protocol are commerciallyavailable (Promega Corp., Madison, Wis., Technical Bulletin TB288).

The assay assesses the ability of compounds to enter cells and inhibitcell proliferation. The assay principle is based on the determination ofthe number of viable cells present by quantitating the ATP present in ahomogenous assay where addition of the Cell Titer-Glo® reagent resultsin cell lysis and generation of a luminescent signal through theluciferase reaction. The luminescent signal is proportional to theamount of ATP present.

Procedure: Day 1—Seed Cell Plates (384-well black, clear bottom,microclear, TC plates with lid from Falcon #353962), Harvest cells, Seedcells at 1000 cells per 54 μl per well into 384 well Cell Plates for 3days assay. Cell Culture Medium: RPMI or DMEM high glucose, 10% FetalBovine Serum, 2 mM L-Glutamine, P/S. Incubate O/N (overnight) at 37° C.,5% CO₂.

Day 2—Add Drug to Cells, Compound Dilution, DMSO Plates (serial 1:2 for9 points). Add 20 μl of compound at 10 mM in the 2nd column of 96 wellplate. Perform serial 1:2 across the plate (10 μl+20 μl 100% DMSO) for atotal of 9 points using Precision Media Plates 96-well conical bottompolypropylene plates from Nunc (cat.#249946) (1:50 dilution). Add 147 μlof Media into all wells. Transfer 3 μl of DMSO+compound from each wellin the DMSO Plate to each corresponding well on Media Plate usingRapidplate® (Caliper, a Perkin-Elmer Co.). For 2 drug combinationstudies, transfer one drug 1.5 μl of DMSO+compound from each well in theDMSO Plate to each corresponding well on Media Plate using Rapidplate.Then, transfer another drug 1.5 μl to the medium plate.

Drug Addition to Cells, Cell Plate (1:10 dilution): Add 6 μl ofmedia+compound directly to cells (54 μl of media on the cells already).Incubate 3 days at 37° C., 5% CO₂ in an incubator that will not beopened often.

Day 5—Develop Plates, Thaw Cell Titer Glo Buffer at room temperature:Remove Cell Plates from 37° C. and equilibrate to room temperature forabout 30 minutes. Add Cell Titer-Glo® Buffer to Cell Titer-Glo®Substrate (bottle to bottle). Add 30 μl Cell Titer-Glo® Reagent (Promegacat.# G7572) to each well of cells. Place on plate shaker for about 30minutes. Read luminescence on Analyst HT Plate Reader (half second perwell). Cell viability assays and combination assays: Cells were seededat 1000-2000 cells/well in 384-well plates for 16 h. On day two, nineserial 1:2 compound dilutions were made in DMSO in a 96 well plate. Thecompounds were further diluted into growth media using a Rapidplate®robot (Zymark Corp., Hopkinton, Mass.). The diluted compounds were thenadded to quadruplicate wells in 384-well cell plates and incubated at37° C. and 5% CO₂. After 4 days, relative numbers of viable cells weremeasured by luminescence using Cell Titer-Glo® (Promega) according tothe manufacturer's instructions and read on a Wallac Multilabel Reader®(PerkinElmer, Foster City). EC50 values were calculated using Prism® 4.0software (GraphPad, San Diego). Drugs in combination assays were dosedstarting at 4×EC₅₀ concentrations. If cases where the EC50 of the drugwas >2.5 μM, the highest concentration used was 10 M. Estrogen receptormodulator compounds and chemotherapeutic agents were addedsimultaneously or separated by 4 hours (one before the other) in allassays.

An additional exemplary in vitro cell proliferation assay includes thefollowing steps:

1. An aliquot of 100 μl of cell culture containing about 10⁴ cells (seeTable 3 for cell lines and tumor type) in medium was deposited in eachwell of a 384-well, opaque-walled plate.

2. Control wells were prepared containing medium and without cells.

3. The compound was added to the experimental wells and incubated for3-5 days.

4. The plates were equilibrated to room temperature for approximately 30minutes.

5. A volume of CellTiter-Glo® Reagent equal to the volume of cellculture medium present in each well was added.

6. The contents were mixed for 2 minutes on an orbital shaker to inducecell lysis.

7. The plate was incubated at room temperature for 10 minutes tostabilize the luminescence signal.

8. Luminescence was recorded and reported in graphs as RLU=relativeluminescence units.

9. Analyze using the Chou and Talalay combination method and Dose-EffectAnalysis with CalcuSyn® software (Biosoft, Cambridge, UK) in order toobtain a Combination Index.

Alternatively, cells were seeded at optimal density in a 96 well plateand incubated for 4 days in the presence of test compound. Alamar Blue™was subsequently added to the assay medium, and cells were incubated for6 h before reading at 544 nm excitation, 590 nm emission. EC₅₀ valueswere calculated using a sigmoidal dose response curve fit.

Alternatively, Proliferation/Viability was analyzed after 48 hr of drugtreatment using Cell Titer-Glo® reagent (Promega Inc., Madison, Wis.).DMSO treatment was used as control in all viability assays. IC₅₀ valueswere calculated using XL fit software (IDBS, Alameda, Calif.)

The cell lines were obtained from either ATCC (American Type CultureCollection, Manassas, Va.) or DSMZ (Deutsche Sammlung vonMikroorganismen und Zellkulturen GmbH, Braunschweig, DE). Cells werecultured in RPMI 1640 medium supplemented with 10% fetal bovine serum,100 units/ml penicillin, 2 mM L-glutamine, and 100 mg/ml streptomycin(Life Technology, Grand Island, N.Y.) at 37° C. under 5% CO₂.

Example 903 MCF7 in vitro cell proliferation assay

MCF7 cells were washed with PBS and plated in RPMI 1640 (Gibco 11835-030[−phenol+glutamine]) and 10% Charcoal Stripped FBS (Gibco 12676-029), inpoly-lysine coated 384 well tissue culture plates (Greiner), at 25,000cells/ml, 40 ul/well, and incubated overnight. Compounds were preparedin serial dilution in DMSO at 500-fold the final desired concentrationusing a Biomek-FX and diluted 50-fold in RPMI 1640. The control compoundfulvestrant and negative control dimethylsulfoxide were also prepared ina similar manner. 5 ul of each individual compound concentration andeach control compound was transferred to the cell plate. Fulvestrant wasadded to control wells at a final concentration of 100 nM). DMSO wasadded to negative control wells (0.2% v/v). Five microliters (5 μl) of 1nM Estradiol (in phenol red free RPMI 1640 (Gibco 11835-030) was addedto each well of the cell plate (except no estradiol control wells).Cells were incubated for 72 hours then lysed using Cell TiterGlo reagent(Promega #G7572) 40 ul/well and the luminescence was measured on anEnvision (Perkin Elmer) plate reader. Data were analyzed using GenedataScreener software, using DMSO and Fulvestrant treated samples to define0% and 100% inhibition and EC50 values were calculated using curvefitting using Robust method.

Example 904 ERa Co-activator Peptide Antagonist Assay

Test compounds were prepared at 1 mM in DMSO and serially diluted in a12 point, 1 to 3-fold titration using a Biomek FX in 384 well clearV-bottom polypropylene plates (Greiner cat #781280). A 3× compoundintermediate dilution was prepared by mixing 1 mL of each concentrationof the compound serial dilution with 32.3 mL of TR-FRET CoregulatorBuffer E (Life Technologies PV4540). 2 mL of the 3× compoundintermediate dilution was transferred to a 1536-well (AuroraBiotechnologies MaKO 1536 Black Plate, #00028905) using a Biomek FX. ABioraptr Dispenser® (Beckman Coulter) was used to dispense: 2 mL perwell of “3×ERa solution”: 22 nM ERa (human estrogen receptor alpha,GST-tagged ESR1 ligand binding domain, spanning residues S282-V595,either wild-type sequence or containing the mutations: Y⁵³⁷S or D538G)in TR-FRET Coregulator Buffer E containing 7.5 mM dithiothreitol (DTT);and 2 mL of 3× Assay mix (750 nM Fluorescein-PGC1a peptide sequence;Life Technologies PV4421), 12 nM Estradiol, 15 nM Anti-GST Tb-labeledantibody in TR-FRET Coregulator Buffer E (with 7.5 mM DTT). “Noreceptor” control wells received buffer without GST-ERa protein. Plateswere centrifuged at 1800 rpm for 20 seconds in V-spin centrifuge andincubated for 2 hours at room temperature with the plates covered.Measurements were made using a Perkin Elmer EnVision Fluorescence Readerusing TR-FRET setting (Top mirror: Perkin Elmer Lance/DELFIA Dualemission (PE #2100-4160); Excitation filter: Perkin Elmer UV (TFR) 340nm (PE #2100-5010); Emission filters: Chroma 495 nm/10 nm and 520 nm/25nm (Chroma#PV003 filters for LanthaScreen, 25 mm diameter for EnVision)Excitation light: 100%; Delay: 100 us; Window time: 200; Number ofsequential windows: 1; Time between flashes: 2000 us; Number of flashes:100; Number of flashes (2^(nd) detector): 100. Percentage inhibitionvalues were calculated relative to no compound (DMSO only) controls anda “no ERa controls”. Curve fitting and IC₅₀ calculations were carriedout using Genedata Screener software.

Example 905 in vivo Mouse Tumor Xenograft Efficacy

Mice: Female severe combined immunodeficiency mice (Fox Chase SCID®,C.B-17/IcrHsd, Harlan) or nude mice (Taconic Farms, Harlan) are 8 to 9weeks old and had a BW range of 15.1 to 21.4 grams on Day 0 of thestudy. The animals are fed ad libitum water (reverse osmosis, 1 ppm Cl)and NIH 31 Modified and Irradiated Lab Diet® consisting of 18.0% crudeprotein, 5.0% crude fat, and 5.0% crude fiber. The mice are housed onirradiated ALPHA-Dri® Bed-O'Cobs® Laboratory Animal Bedding in staticmicroisolators on a 12-hour light cycle at 21-22° C. (70-72° F.) and40-60% humidity. PRC specifically complies with the recommendations ofthe Guide for Care and Use of Laboratory Animals with respect torestraint, husbandry, surgical procedures, feed and fluid regulation,and veterinary care. The animal care and use program at PRC isaccredited by the Association for Assessment and Accreditation ofLaboratory Animal Care International (AAALAC), which assures compliancewith accepted standards for the care and use of laboratory animals.

Tumor Implantation: Xenografts are initiated with cancer cells. Cellsare cultured in RPMI 1640 medium supplemented with 10% fetal bovineserum, 2 mM glutamine, 100 units/mL penicillin, 100 μg/mL streptomycinsulfate and 25 μg/mL gentamicin. The cells are harvested duringexponential growth and resuspended in phosphate buffered saline (PBS) ata concentration of 5×10⁶ or 10×10⁶ cells/mL depending on the doublingtime of the cell line. Tumor cells are implanted subcutaneously in theright flank, and tumor growth is monitored as the average sizeapproached the target range of 100 to 150 mm3. Twenty-one days aftertumor implantation, designated as Day 0 of the study, the mice areplaced into four groups each consisting of ten mice with individualtumor volumes ranging from 75-172 mm3 and group mean tumor volumes from120-121 mm3 (see Appendix A). Volume is calculated using the formula:

Tumor Volume (mm³)=(w²×l)/2, where w=width and 1=length in mm of atumor. Tumor weight may be estimated with the assumption that 1 mg isequivalent to 1 mm3 of tumor volume.

Therapeutic Agents: Estrogen receptor modulator compounds andchemotherapeutic agents are typically prepared from dry powders, storedat room temperature, and protected from light. Drug doses are preparedweekly in 0.5% methylcellulose: 0.2% Tween 80 in deionized water(“Vehicle”) and stored at 4° C. Vehicle (+) is solvent/buffer withethynyl estradiol (ethinyl estradiol, EE2) at 0.1 mg/kg. Vehicle (−) issolvent/buffer without ethynyl estradiol. Doses of compounds areprepared on each day of dosing by diluting an aliquot of the stock withsterile saline (0.9% NaCl). All doses are formulated to deliver thestated mg/kg dosage in a volume of 0.2 mL per 20 grams of body weight(10 mL/kg).

Treatment: All doses are scaled to the body weights of the individualanimals and provided by the route indicated.

Endpoint: Tumor volume is measured in 2 dimensions (length and width),using Ultra Cal IV calipers (Model 54 10 111; Fred V. Fowler Company),as follows: tumor volume (mm³)=(length×width²)×0.5 and analyzed usingExcel version 11.2 (Microsoft Corporation). A linear mixed effect (LME)modeling approach is used to analyze the repeated measurement of tumorvolumes from the same animals over time (Pinheiro J, et al. nlme: linearand nonlinear mixed effects models. R package version 3.1 92. 2009; TanN, et al. Clin. Cancer Res. 2011; 17(6): 1394-1404). This approachaddresses both repeated measurements and modest dropouts due to anynon-treatment-related death of animals before study end. Cubicregression splines are used to fit a nonlinear profile to the timecourses of log 2 tumor volume at each dose level. These nonlinearprofiles are then related to dose within the mixed model. Tumor growthinhibition as a percentage of vehicle control (% TGI) is calculated asthe percentage of the area under the fitted curve (AUC) for therespective dose group per day in relation to the vehicle, using thefollowing formula: % TGI=100×(1−AUC_(dose)/AUC_(veh)). Using thisformula, a TGI value of 100% indicates tumor stasis, a TGI value of >1%but <100% indicates tumor growth delay, and a TGI value of >100%indicates tumor regression. Partial response (PR) for an animal isdefined as a tumor regression of >50% but <100% of the starting tumorvolume. Complete response (CR) was defined as 100% tumor regression(i.e., no measurable tumor) on any day during the study.

Toxicity: Animals are weighed daily for the first five days of the studyand twice weekly thereafter. Animal body weights are measured using anAdventurer Pro® AV812 scale (Ohaus Corporation). Percent weight changeis calculated as follows: body weight change(%)=[(weight_(day new)−weight_(day 0))/weight_(day 0)]×100. The mice areobserved frequently for overt signs of any adverse, treatment-relatedside effects, and clinical signs of toxicity recorded when observed.Acceptable toxicity is defined as a group mean body weight (BW) loss ofless than 20% during the study and not more than one treatment-related(TR) death among ten treated animals. Any dosing regimen that results ingreater toxicity is considered above the maximum tolerated dose (MTD). Adeath is classified as TR if attributable to treatment side effects asevidenced by clinical signs and/or necropsy, or may also be classifiedas TR if due to unknown causes during the dosing period or within 10days of the last dose. A death is classified as NTR if there is noevidence that death was related to treatment side effects.

In-Vivo Xenograft Breast Cancer Model; (MCF-7; Tamoxifen-Sensitive):

Time release pellets containing 0.72 mg 17-β Estradiol aresubcutaneously implanted into nu/nu mice. MCF-7 cells were grown in RPMIcontaining 10% FBS at 5% CO₂, 37° C.

Trypsinized cells are pelleted and re-suspended in 50% RPMI (serum free)and 50% Matrigel at 1×10⁷ cells/mL. MCF-7 cells are subcutaneouslyinjected (100 μL/animal) on the right flank 2-3 days post pelletimplantation. Tumor volume (length×width²/2) is monitored bi-weekly.When tumors reach an average volume of −200 mm³ animals are randomizedand treatment is started. Animals are treated with vehicle or compounddaily for 4 weeks. Tumor volume and body weight are monitored bi-weeklythroughout the study.

In-Vivo Xenograft Breast Cancer Model; (Tamoxifen-Resistant Model):

Female nu/nu mice (with supplemental 17-0 Estradiol pellets; 0.72 mg; 60day slow release) bearing MCF-7 tumors (mean tumor volume 200 mm³) aretreated with tamoxifen (citrate) by oral gavage. Tumor volume(length×width²/2) and body weight are monitored twice weekly. Followinga significant anti-tumor response in which tumor volume remained static,evident tumor growth is first observed at approximately 100 days oftreatment. At 120 days of treatment, tamoxifen dose is increased.Rapidly growing tumors are deemed tamoxifen resistant and selected forin vivo passage into new host animals. Tumor Fragments (˜100 mm³/animal)from the tamoxifen resistant tumors are subcutaneously implanted intothe right flank of female nu/nu mice (with 17-β Estradiol pellets (0.72mg; 60 day slow release)). Passaged tumors are maintained under constantTamoxifen selection, and tumor volume (length×width²/2) is monitoredweekly. When tumor volume reached ˜150-250 mm³, animals are randomizedinto treatment groups (mean tumor volume 200 mm³) and tamoxifentreatment is terminated. Animals are treated with vehicle or compounddaily for 4 weeks. Tumor volume and body weight are monitored twiceweekly for the duration of the study.

Example 906 Immature Uterine Wet Weight Assay

Female immature CD-IGS rats (21 days old upon arrival) are treated forthree days. Animals are dosed daily for three days. For Antagonist Mode,Vehicle or test compound is administered orally by gavage followed 15minutes later by an oral dose of 0.1 mg/kg Ethynyl Estradiol. ForAgonist Mode, Vehicle or test compound is administered orally by gavage.On the fourth day 24 hours after dose, plasma is collected forpharmacokinetic analysis. Immediately following plasma collection, theanimals are euthanized and the uterus removed and weighed.

Example 907 Adult Uterine Wet Weight-10 Day Assay

Female CD-IGS rats (69 days old, Charles River Laboratories) arepurchased and split into groups. Group 1 is ovariectomized at the vendor(Charles River Laboratories) at 60 days of age and the study is started2 weeks after surgery, while groups 2-8 were intact. Vehicle or testcompound is administered orally for 10 days. Two hours after the 10^(th)and final dose, cardiac punctures are performed and serum is collectedfor pharmacokinetic and estradiol analyses. Immediately following serumcollection, the animals are euthanized and the uterus and ovariesremoved and weighed. Uteri and ovaries from 2 animals per group arefixed in 10% neutral buffered formalin and paraffin embedded, sectionedand stained for H&E (SDPath). Stained tissues are analyzed and read by aboard certified pathologist. Uteri and ovaries from 4 animals per groupare flash frozen in liquid N₂ for transcriptional analysis, examining aselect set of genes modulated by the estrogen receptor.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, the descriptions and examples should not be construed aslimiting the scope of the invention. The disclosures of all patent andscientific literature cited herein are expressly incorporated in theirentirety by reference.

We claim:
 1. A compound of Formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:Y¹ is CR^(b) or N; Y² is —(CH₂)—, —(CH₂CH₂)—, or NR^(a); Y³ is NR^(a) orC(R^(b))₂; where one of Y¹, Y² and Y³ is N or NR^(a); R^(a) and R^(c)are independently H, C₁-C₆ alkyl, C₁-C₆ fluoroalkyl, allyl, propargyl,C₃-C₆ cycloalkyl, or C₃-C₆ heterocyclyl, optionally substituted with oneor more groups independently selected from the group consisting of F,Cl, Br, I, CN, OH, OCH₃, and SO₂CH₃; R^(b) is independently H, —O(C₁-C₃alkyl), C₁-C₆ alkyl, C₁-C₆ fluoroalkyl, allyl, propargyl, C₃-C₆cycloalkyl, or C₃-C₆ heterocyclyl, optionally substituted with one ormore groups independently selected from the group consisting of F, Cl,Br, I, CN, OH, OCH₃, and SO₂CH₃, where at least one of R^(a) and R^(b)is —CH₂Cl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, CH₂CH₂Cl,CH₂CH₂CH₂F, CH₂CH₂CHF₂, CH₂CH₂CF₃, or CH₂CH₂CH₂Cl; X¹, X², X³, and X⁴are independently CH, CR⁵ or N; where none, one, or two of X¹, X², X³,and X⁴ is N; Z is O, S, S(O), S(O)₂, C(═O), CH(OH), C₁-C₆ alkyldiyl,CH(OH)—(C₁-C₆ alkyldiyl), C₁-C₆ fluoroalkyldiyl, NR^(c)—(C₁-C₆alkyldiyl), NR^(c)—(C₁-C₆ fluoroalkyldiyl), O—(C₁-C₆ alkyldiyl), orO—(C₁-C₆ fluoroalkyldiyl); R¹ and R² are independently H, F, Cl, Br, I,—CN, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂OCH₃,—CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃,—CH₂OP(O)(OH)₂, —CH₂Cl, —CH₂F, —CHF₂, —CH₂NH₂, —CH₂NHSO₂CH₃, —CH₂NHCH₃,—CH₂N(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH(CH₃)CN, —C(CH₃)₂CN, —CH₂CN,—CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂, —CONHCH₃,—CONHCH₂CH₃, —CONHCH(CH₃)₂, —CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂, —NHCH₃,—N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃, —N(CH₃)C(CH₃)₂CONH₂,—N(CH₃)CH₂CH₂S(O)₂CH₃, —NO₂, ═O, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OCH₃,—OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂, —S(O)₂N(CH₃)₂, —SCH₃,—S(O)₂CH₃, —S(O)₃H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl,azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino,azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl,pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl,morpholino-methanone, or morpholino; R³ is C₃-C₂₀ cycloalkyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, C₁-C₂₀ heteroaryl, —(C₁-C₆ alkyldiyl)-(C₃-C₂₀cycloalkyl), —(C₁-C₆ alkyldiyl)-(C₂-C₂₀ heterocyclyl), —(C₁-C₆alkyldiyl)-(C₆-C₂₀ aryl), or —(C₁-C₆ alkyldiyl)-(C₁-C₂₀ heteroaryl); orR³ forms a 3-6-membered spiro carbocyclic or heterocyclic group; R⁴ andR⁵ are independently F, Cl, Br, I, —CN, —CH₃, —CH₂CH₃, —CH(CH₃)₂,—CH₂CH(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂,—C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃, —CH₂OP(O)(OH)₂, —CH₂F, —CHF₂, —CH₂NH₂,—CH₂NHSO₂CH₃, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH(CH₃)CN, —C(CH₃)₂CN, —CH₂CN, —CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃,—COCH(OH)CH₃, —CONH₂, —CONHCH₃, —CONHCH₂CH₃, —CONHCH(CH₃)₂, —CON(CH₃)₂,—C(CH₃)₂CONH₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃,—NHS(O)₂CH₃, —N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃, —NO₂, ═O, —OH,—OCH₃, —OCH₂CH₃, —OCH₂CH₂OCH₃, —OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂,—S(O)₂N(CH₃)₂, —SCH₃, —S(O)₂CH₃, —S(O)₃H, cyclopropyl, cyclopropylamide,cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy,N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl,pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl,morpholinomethyl, morpholino-methanone, or morpholino; and m is 0, 1, 2,3, or 4; where alkyldiyl, fluoroalkyldiyl, aryl, carbocyclyl,heterocyclyl, and heteroaryl are optionally substituted with one or moregroups independently the group consisting of F, Cl, Br, I, —CN, —CH₃,—CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH,—C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃,—CH₂OP(O)(OH)₂, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH(CH₃)CN,—C(CH₃)₂CN, —CH₂CN, —CH₂NH₂, —CH₂NHSO₂CH₃, —CH₂NHCH₃, —CH₂N(CH₃)₂,—CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂, —CONHCH₃,—CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHCOCH₃,—N(CH₃)COCH₃, —NHS(O)₂CH₃, —N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃,—NO₂, ═O, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OCH₃, —OCH₂CH₂OH,—OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂, —S(O)₂N(CH₃)₂, —SCH₃, —S(O)₂CH₃, —S(O)₃H,cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl,1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino,azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl,pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl,morpholino-methanone, and morpholino.
 2. The compound orpharmaceutically acceptable salt thereof of claim 1 having Formula Ia:

wherein n is 0, 1, 2, 3, or
 4. 3. The compound or pharmaceuticallyacceptable salt thereof of claim 2 having Formula Ib:

wherein R⁶ is F, Cl, Br, I, —CN, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂,—CH₂OH, —CH₂OCH₃, —CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH,—CH₂CH₂SO₂CH₃, —CH₂OP(O)(OH)₂, —CH₂F, —CHF₂, —CH₂NH₂, —CH₂NHSO₂CH₃,—CH₂NHCH₃, —CH₂N(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH(CH₃)CN, —C(CH₃)₂CN,—CH₂CN, —CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂,—CONHCH₃, —CONHCH₂CH₃, —CONHCH(CH₃)₂, —CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂,—NHCH₃, —N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃,—N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃, —NO₂, ═O, —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂OCH₃, —OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂,—S(O)₂N(CH₃)₂, —SCH₃, —S(O)₂CH₃, —S(O)₃H, cyclopropyl, cyclopropylamide,oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy,N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl,pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl,morpholinomethyl, morpholino-methanone, or morpholino; and p is selectedfrom 0, 1, 2, 3, or
 4. 4. The compound or pharmaceutically acceptablesalt thereof of claim 1 having Formula Ic:

wherein n is 0, 1, 2, 3, or
 4. 5. The compound or pharmaceuticallyacceptable salt thereof of claim 4 having Formula Id:

wherein R^(a) is —CH₂Cl, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, or —CH₂CF₃. 6.The compound or pharmaceutically acceptable salt thereof of claim 1having Formula Ie:

wherein n is 0, 1, 2, 3, or
 4. 7. The compound or pharmaceuticallyacceptable salt thereof of claim 6 having Formula If:

wherein IV is —CH₂Cl, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, or —CH₂CF₃. 8.The compound or pharmaceutically acceptable salt thereof of claim 1having Formula Ig:

wherein n is 0, 1, 2, 3, or
 4. 9. The compound or pharmaceuticallyacceptable salt thereof of claim 1 having Formula Ih:

wherein n is 0, 1, 2, 3, or
 4. 10. The compound or pharmaceuticallyacceptable salt thereof of claim 1 selected from Formula Ii or FormulaIj:


11. The compound or pharmaceutically acceptable salt thereof of claim 1wherein R^(a) is —CH₂Cl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, or—CH₂CF₃.
 12. The compound or pharmaceutically acceptable salt thereof ofclaim 1 wherein Y¹ is CR^(b) and Y³ is NR^(a).
 13. The compound orpharmaceutically acceptable salt thereof of claim 1 wherein Y¹ is N andY³ is C(R^(b))₂.
 14. The compound or pharmaceutically acceptable saltthereof of claim 1 wherein Y² is —(CH₂)—.
 15. The compound orpharmaceutically acceptable salt thereof of claim 1 wherein Y² is—(CH₂CH₂)—.
 16. The compound or pharmaceutically acceptable salt thereofof claim 1 wherein Y³ is NR^(a) and R^(a) is —CH₂Cl, —CH₂F, —CHF₂, —CF₃,—CH₂CH₂F, —CH₂CHF₂, or —CH₂CF₃.
 17. The compound or pharmaceuticallyacceptable salt thereof of claim 1 wherein X¹, X², X³, and X⁴ areindependently CH or CR⁵.
 18. The compound or pharmaceutically acceptablesalt thereof of claim 1 wherein one of X¹, X², X³, and X⁴ is N.
 19. Thecompound or pharmaceutically acceptable salt thereof of claim 1 whereinZ is O or O—(C₁-C₆ alkyldiyl).
 20. The compound or pharmaceuticallyacceptable salt thereof of claim 1 wherein R¹ and R² are H.
 21. Thecompound or pharmaceutically acceptable salt thereof of claim 1 whereinR³ is C₆-C₂₀ aryl.
 22. The compound or pharmaceutically acceptable saltthereof of claim 21 wherein C₆-C₂₀ aryl is phenyl.
 23. The compound orpharmaceutically acceptable salt thereof of claim 22 wherein phenyl issubstituted with one or more F.
 24. The compound or pharmaceuticallyacceptable salt thereof of claim 1 wherein R⁴ is OH, and m is
 1. 25. Thecompound or pharmaceutically acceptable salt thereof of claim 1 whereinR⁵ is F and n is
 2. 26. The compound or pharmaceutically acceptable saltthereof of claim 1 wherein R⁵ is H.
 27. The compound or pharmaceuticallyacceptable salt thereof of claim 1 wherein n is
 0. 28. The compound orpharmaceutically acceptable salt thereof of claim 1 selected from thegroup consisting of:(1R,2S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-phenyl-tetralin-6-ol;(1S,2R)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-phenyl-tetralin-6-ol;(1S,2R)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(4-fluorophenyl)tetralin-6-ol;(1R,2R)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-phenyl-tetralin-6-ol;(1S,2S)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-phenyl-tetralin-6-ol;(1R,2S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(4-fluorophenyl)tetralin-6-ol;(5R,6R)-5-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydronaphthalen-2-ol;(5S,6S)-6-(4,4-difluorocyclohexyl)-5-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol;(5S,6S)-5-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydronaphthalen-2-ol;(5R,6R)-6-(4,4-difluorocyclohexyl)-5-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol;(5R,6S)-5-(4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5R,6S)-5-(4-(2-(3-(chloromethyl)azetidin-1-yl)ethoxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5S,6R)-5-(4-(2-(3-(chloromethyl)azetidin-1-yl)ethoxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5S,6R)-5-(4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5S,6R)-5-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-(4-(methylsulfonyl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol;(5S,6R)-5-(4-(2-(3-(difluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5R,6S)-5-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-(4-(methylsulfonyl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol;(5R,6S)-5-(4-(2-(3-(difluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5R,6R)-5-(2-fluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5S,6S)-5-(2-fluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(S)-1′-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3′,4′-dihydro-1′H-spiro[cyclopentane-1,2′-naphthalen]-6′-ol;(R)-1‘-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3’,4′-dihydro-1‘H-spiro[cyclopentane-1,2’-naphthalen]-6′-ol;(5R,6S)-5-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5S,6R)-5-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5R,6S)-5-(4-(((R)-1-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propan-2-yl)oxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5S,6R)-5-(4-(((R)-1-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propan-2-yl)oxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5S,6S)-5-(6-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)pyridin-3-yl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5R,6R)-5-(6-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)pyridin-3-yl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5S,6R)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5R,6S)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5S,6R)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;and(5R,6S)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol,or a pharmaceutically acceptable salt thereof.
 29. The compound orpharmaceutically acceptable salt thereof of claim 1 selected from thegroup consisting of:4-((1R,2S)-1-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)benzonitrile;4-((1S,2R)-1-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)benzonitrile;(7S,8R)-8-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-7-phenyl-5,6,7,8-tetrahydronaphthalen-1-ol;(7R,8S)-8-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-7-phenyl-5,6,7,8-tetrahydronaphthalen-1-ol;(5R,6S)-5-(4-((2-(3-(fluoromethyl)azetidin-1-yl)ethyl)amino)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5S,6R)-5-(4-((2-(3-(fluoromethyl)azetidin-1-yl)ethyl)amino)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5R,6S)-5-(4-((2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethyl)amino)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;and(5S,6R)-5-(4-((2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethyl)amino)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol,or a pharmaceutically acceptable salt thereof.
 30. A pharmaceuticalcomposition comprised of a compound or pharmaceutically acceptable saltthereof of claim 1, and one or more pharmaceutically acceptableexcipients.
 31. A kit for treating a condition mediated by an estrogenreceptor, breast cancer, the kit comprising: a) a pharmaceuticalcomposition of claim 30; and b) instructions for use.
 32. The kit ofclaim 31, wherein the breast cancer is hormone dependent breast cancer,ER dependent breast cancer, estrogen-sensitive breast cancer, or hormonereceptor positive metastatic breast cancer.
 33. The kit of claim 31,wherein the kit further comprises a second anti-cancer agent comprisingraloxifene, droloxifene, tamoxifen, 4-hydroxytamoxifen,trioxifene,keoxifene, fulvestrant, exemestane, vorozole, letrozole, or anastrozole.34. A compound or pharmaceutically acceptable salt thereof selected fromthe group consisting of:(1R,2S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-phenyl-tetralin-6-ol;(1S,2S)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-phenyl-tetralin-6-ol;and(5R,6S)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;or a pharmaceutically acceptable salt thereof.
 35. A pharmaceuticalcomposition comprising a compound or pharmaceutically acceptable saltthereof of claim 34 and one or more pharmaceutically acceptableexcipients.